Podcasts about missense

“The grant will fund the computational analysis of SYNGAP1  missense variants and the construction of an online server called SynGAP Missense (SGM) server providing clinicians and others open access to the modeling and bioinformatics results.”   Types of mutations https://youtu.be/xYOK-yzUWSI    SYNGAP1 on Alphafold https://alphafold.ebi.ac.uk/entry/F6SEU4    Dr. Underbake on Disordered/Unstructured Proteins https://youtu.be/Q11q_m_tV88?si=Ix9Gr7RSiCdFCgqH&t=830    Common Missense https://www.syngapresearchfund.org/post/syngap1-frequent-de-novo-missense-variant-alert-study-opportunity-for-p-gly344    Young c.980T>C p.Leu327Pro http://clinvar.com/ SYNGAP1 c.980C>T 2015 UK https://pubmed.ncbi.nlm.nih.gov/26079862/ 2018 SK https://pubmed.ncbi.nlm.nih.gov/29390993/    SRF iPSCs https://www.syngapresearchfund.org/post/another-srf-contribution-to-syngap1-research-patient-derived-cell-lines-to-test-treatments    Dr. Courtney Grant https://www.eurekalert.org/news-releases/957967    Dr. Courtney Webinar https://www.syngapresearchfund.org/webinars/79-quantifying-perturbed-syngap1-function-caused-by-coding-mutations    Dr. Haas Webinar https://www.syngapresearchfund.org/webinars/functional-assessment-of-missense-variants-of-syngap1-kurt-haas    EpiMVP https://epimvp.med.umich.edu/    https://leonandfriends.org/ started this work https://www.syngapresearchfund.org/leon  #S10e73 https://www.youtube.com/watch?v=FJgXP4l0cuk    Register for the Conference! 35 Days until the Conference - Sign up by Halloween. https://secure.givelively.org/event/syngap-research-fund-incorporated/syngap1-conference-2023-hosted-by-syngap-research-fund-srf   #SyngapConf Conference Agenda Announced! #S10e120 described the agenda… https://www.youtube.com/watch?v=Q9U-Ggz_K2I  Press release  https://www.syngapresearchfund.org/post/uniting-for-progress-the-fifth-annual-syngap1-conference-hosted-by-syngap-research-fund-srf-will-take-place-november-30th-in-orlando-florida-syngapconf    Give all three of our podcasts 5 stars everywhere.   https://podcasts.apple.com/us/channel/syngap1-podcasts-by-srf/id6464522917    This is a podcast subscribe! https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1/id1560389818 Episode 121 of #Syngap10 - October 25, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat

Happy 5th Birthday SRF! https://mailchi.mp/syngapresearchfund.org/happy-5th-birthday-srf  FASTERCURES See #S10e98 https://www.youtube.com/watch?v=iOLjUdVUtqo  https://milkeninstitute.org/centers/fastercures/building-nonprofit-capacity/train  Census https://Syngap.fund/census - 1,238 CHOP McKee Grant via AES https://twitter.com/jillianlmckee/status/1674037974684647424?s=46&t=8Y3-Ue9XY-QOTy42vH52Fw  NHS Blog - https://www.syngapresearchfund.org/post/natural-history-study-at-childrens-hospital-of-philadelphia-is-a-natural-win-for-srf  What to expect - https://www.syngapresearchfund.org/post/what-to-expect-when-youre-preparing-to-visit-the-syngap1-natural-history-study  Their reflections: http://epilepsygenetics.net/2023/07/11/stxbp1-and-syngap1-natural-history-reflections-after-day-1-of-endd-clinic/ STUDIES See #S10e107 for four opportunities, https://www.youtube.com/watch?v=boHYLi3S-Mk  But also: UCLA - EEG - West Coast! Missense, let's make cell lines… watch this: https://www.syngapresearchfund.org/webinars/79-quantifying-perturbed-syngap1-function-caused-by-coding-mutations/  PODCASTS Brain and Life 1 and 2 https://www.brainandlife.org/articles/after-their-children-were-diagnosed-with  Part 1 - English - https://www.brainandlife.org/podcast/community-stories-navigating-rare-epilepsy-diagnosis  Part 2 - Spanish - https://www.brainandlife.org/podcast/comunidad-sobre-como-afrontar-diagnostico-epilepsia-genetica  Podcasts - Syngap1 Stories - Ashley Evans (11) and Monica Harding (12) Ashley - https://www.syngapresearchfund.org/podcast-episodes/syngap1-stories-episode-011 Monica - https://www.syngapresearchfund.org/podcast-episodes/syngap1-stories-episode-012 CONFERENCE  Pre-registration link: https://Syngap.Fund/2023conf   Hotels ASAP: https://Syngap.Fund/2023hotel  Merch https://www.bonfire.com/srf-syngap1-conference-2023/  All this was in today's newsletter! https://Syngap.Fund/News33  Ed is doing a great job with these, thank you Ed! Volunteer with SRF! Info@SyngapResearchFund.org  This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here  - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts:  https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 108 of #Syngap10 - July 13, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Happy 5th Birthday SRF! https://mailchi.mp/syngapresearchfund.org/happy-5th-birthday-srf    FASTERCURES See #S10e98 https://www.youtube.com/watch?v=iOLjUdVUtqo  https://milkeninstitute.org/centers/fastercures/building-nonprofit-capacity/train  Census https://Syngap.fund/census - 1,238   CHOP McKee Grant via AES https://twitter.com/jillianlmckee/status/1674037974684647424?s=46&t=8Y3-Ue9XY-QOTy42vH52Fw  NHS Blog - https://www.syngapresearchfund.org/post/natural-history-study-at-childrens-hospital-of-philadelphia-is-a-natural-win-for-srf  What to expect - https://www.syngapresearchfund.org/post/what-to-expect-when-youre-preparing-to-visit-the-syngap1-natural-history-study  Their reflections: http://epilepsygenetics.net/2023/07/11/stxbp1-and-syngap1-natural-history-reflections-after-day-1-of-endd-clinic/   STUDIES See #S10e107 for four opportunities, https://www.youtube.com/watch?v=boHYLi3S-Mk  But also: UCLA - EEG - West Coast! Missense, let's make cell lines… watch this: https://www.syngapresearchfund.org/webinars/79-quantifying-perturbed-syngap1-function-caused-by-coding-mutations/    PODCASTS Brain and Life 1 and 2 https://www.brainandlife.org/articles/after-their-children-were-diagnosed-with  Part 1 - English - https://www.brainandlife.org/podcast/community-stories-navigating-rare-epilepsy-diagnosis  Part 2 - Spanish - https://www.brainandlife.org/podcast/comunidad-sobre-como-afrontar-diagnostico-epilepsia-genetica    Podcasts - Syngap1 Stories - Ashley Evans (11) and Monica Harding (12) Ashley - https://www.syngapresearchfund.org/podcast-episodes/syngap1-stories-episode-011 Monica - https://www.syngapresearchfund.org/podcast-episodes/syngap1-stories-episode-012   CONFERENCE  Pre-registration link: https://Syngap.Fund/2023conf   Hotels ASAP: https://Syngap.Fund/2023hotel  Merch https://www.bonfire.com/srf-syngap1-conference-2023/    All this was in today's newsletter! https://Syngap.Fund/News33    Ed is doing a great job with these, thank you Ed!   Volunteer with SRF! Info@SyngapResearchFund.org    This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here  - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts:  https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 108 of #Syngap10 - July 13, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat

Let's grant for the moment that somehow, the fully functional and the irreducibly complex genetic code necessary for a single eukaryotic, or even prokaryotic cell, came into existence by happenstance (or by panspermia, perhaps, or by an infinite number of parallel universes -- pick your deus ex machina mechanism). Even with a "cheat" like this, could the evolutionary process take it from there? Spontaneous genetic point mutations, in which one of the four DNA base pairs is swapped for another, do occur from time to time, at a rate of around 1.1×10−8 (https://academic.oup.com/genetics/article/156/1/297/6051861?login=false) per base pair per generation (that's one in 100 million). However the vast majority of these are either negative or neutral. They're typically neutral if they occur in the non-coding segment of DNA, which is not used as blueprints for proteins. (We're still not entirely sure what the purpose is of all this non-coding DNA. There was a time when all of it was thought to be "junk," or leftovers from previous evolutionary steps. Now we know that at least some of it serves a purpose: of regulation, saying when a given sequence should or shouldn't be transcribed, where the coding gene begins and ends, binding sites for the transcription mechanism to begin, kind of like the coupling component of a zipper, and things like that. Telomeres, the caps on our chromosomes now known to be one of the determining factors of biological age, are also part of non-coding DNA. Other segments of it protect the structure of the chromosomes so that they maintain their integrity during cell replication. No doubt more purposes will be understood in time, but I seriously doubt any of it will turn out to be "junk"). Negative DNA mutations in coding sequences is one of the mechanisms by which cancer occurs. These can be either "nonsense" or "missense" mutations. Nonsense mutations are when a point mutation forms what's called a "stop" codon (where a codon is a set of three base pairs, forming a "word" of sorts.) Rather that continuing to code for a protein, the stop codon in the middle of the sequence would simply prematurely truncate the protein code entirely. Missense mutations occur when a point mutation switches one codon to another... like turning "cat" into "bat" or "rat," with an entirely different meaning. Each codon calls for a different amino acid, so such a mutation may substitute a different one with different chemical properties, which (if those properties are different enough) might contribute to different stereochemistry, or folding of that protein once made. The stereochemistry largely determines the protein's function, so it might be thus altered (and nearly always for the worse)... though there are are redundancies, such that multiple codons call for the same amino acids (there are only twenty amino acids, after all). So it's possible the mutation might be "silent" even if in a coding sequence of DNA, in this case. Environmental factors known to increase DNA mutation rates include things like ionizing radiation (UV, x-ray, gamma ray, etc), and various carcinogenic chemicals. If these mutations occur in germ cells, they can be passed on to progeny, assuming that the mutation isn't rapidly fatal before it can be passed on. In some cases, the resulting "disease" may confer a survival advantage in a given environment--for example, sickle cell anemia, a point mutation that changes the shape of red blood cells. It does indeed cause severe disease, but it also happens to protect against malaria, endemic in Africa. This is probably why sickle cell is far more common in Africa that in other parts of the world. But it's quite a stretch to say that was a "positive" mutation. Sickle cell anemia manifests with recurrent hemolytic crises, in which red blood cells burst, leading to severe low levels in the bloodstream (which means not enough oxygen for the tissues). Red blood cells can also get stuck in small vessels, leading to clots, spleen and liver enlargement, etc. Sure, the mutation happens to have a survival benefit in Africa, but "positive," the way a sudden functioning eye might be? I don't think so. And that's the thing: we can't point to a single known unequivocally positive DNA mutation. The most we can do is identify some "bad" ones that happen to have a silver lining in a particular environment. From there, evolutionists extrapolate (tremendously!) that in the distant past, many such mutations must have occurred--even though we have no evidence that they did, and all evidence we do have seems to suggest otherwise. I've seen some sources that speculate that positive mutations occur about 1/1000 times per generation, though the paper, "The population genetics of mutations: good, bad, and indifferent" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871823/) makes the point that this is an exceedingly difficult number to quantify, because how one mutation might interact with another, let alone how multiple mutations might interact in a larger organism, is so very complex. Nevertheless, if we go with the 1/1000 number (which seems like as reasonable an estimate as any), since any sort of genetic mutation (a point mutation anyway) is supposed to occur only 1/100 million times per generation, that means a single positive mutation might occur 1/100 billion times per generation. Since earth is estimated to be 4.54 billion years old, and a generation is usually defined to be about 20 years, that's 225 million generations since the dawn of earth's time, by secular calculations. Do you see the problem here? If those estimations are even in the ballpark, there hasn't been enough time statistically for even one unequivocally positive mutation to occur. The universe literally doesn't have enough time for evolution to occur (unless you introduce multiple universes... and even then, you'd need a near infinite number of them).See omnystudio.com/listener for privacy information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.01.547348v1?rss=1 Authors: Fazeli, E., Child, D. D., Bucks, S. A., Stovarsky, M., Edwards, G., Yu, C.-E., Latimer, C., Kitago, Y., Bird, T., Jayadev, S., Young, J. E. Abstract: The SORL1 gene has recently emerged as a strong Alzheimer Disease risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still unknown. Here, we describe a multi-generational family with both early- and late-onset AD in two generations. Exome sequencing identified a coding variant, p.(Arg953Cys), in SORL1 in 4 of 5 individuals affected by AD. Notably, variant carriers had severe AD pathology, including the presence of Ab plaques in the cerebellum as well as TDP-43 pathology. We further characterized this variant and show that this Arginine substitution occurs at a critical domain position of the SORL1 translation product, SORL1. In vitro studies further show that the SORL1 p.R953C variant has decreased maturation and shedding of the SORL1 protein, and also leads to mis-localization within cells. Together, our analysis suggests that p.R953C is a likely pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr Isabelle Adant follows up on a recent review on ATP7A with the case of a neonate presenting with occipital horn syndrome. Neonatal presentation of occipital horn syndrome caused by a ATP7A missense variant Isabelle Adant, et al https://doi.org/10.1002/jimd.12621

Professor Jayesh Sheth discusses two patients diagnosed with MLD following milder presentations, both related to novel missense variants in the PSAP gene. Late infantile and adult-onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India Jayesh Sheth, et al https://doi.org/10.1002/jmd2.12374

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.09.536174v1?rss=1 Authors: Gregory, E. F., Kalra, S., Brock, T., Bonne, G., Luxton, G. G., Hopkins, C., Starr, D. A. Abstract: Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.05.531173v1?rss=1 Authors: Martin, S. C. T., Qadota, H., Oberhauser, A. F., Hardin, J., Benian, G. M. Abstract: Protein phosphatase 2A (PP2A) functions in a variety of cellular contexts. PP2A can assemble into four different complexes based on the inclusion of different regulatory or targeting subunits. The regulatory subunit striatin forms the STRIPAK complex consisting of striatin, a catalytic subunit (PP2AC), striatin interacting protein 1 (STRIP1), and MOB family member 4 (MOB4). In yeast and C. elegans, STRIP1 is required for formation of the endoplasmic reticulum (ER). Since the sarcoplasmic reticulum (SR) is the highly organized muscle-specific version of ER, we sought to determine the function of the STRIPAK complex in muscle using C. elegans. CASH-1 (striatin) and FARL-11 (STRIP1/2) form a complex in vivo, and each protein is localized to SR. Missense mutations and single amino acid losses in farl-11 and cash-1 each result in similar sarcomere disorganization. A missense mutation in farl-11 shows no detectable FARL-11 protein by immunoblot, disruption of SR organization around M-lines, and altered levels of the SR Ca+2 release channel UNC-68. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

It's RARE DISEASE DAY! Hattie has a new video! https://www.syngapresearchfund.org/families/movies I'm off to DC for NIH Day and RD Advocacy with Everylife Foundation - https://ncats.nih.gov/news/events/rdd - https://everylifefoundation.org/rare-advocates/rare-disease-week/ We have a $20k match! - https://syngap.fund/rdd23 - https://secure.givelively.org/donate/syngap-research-fund-incorporated/srf-rare-disease-day-2023 Deadline for Grants is 3/1 - https://www.syngapresearchfund.org/post/134-apply-for-syngap1-research-grants-by-march-1st-or-september-1st #Sprint4Syngap - https://syngap.fund/sprint23 - Main page https://secure.givelively.org/donate/syngap-research-fund-incorporated/sprint4syngap-2023 - 15 Teams! Eight already raising funds: Team Tavilla, Emma Mae, Reef, Kai, Naya, Hope4Hadley, Teddy & Lizzy. Seven more ready to go. - Remember, there is an adaptive bike in play! - New family has an event to go to… COMMUNITY Amazing Webinars - Jeff Coller - mRNA - March 16th https://www.syngapresearchfund.org/webinars/68-harnessing-messenger-rna-metabolism-for-the-development-of-precision-gene-therapy-syngap1 - Jillian McKee - April 27th - https://syngap.fund/mckee Ciitizen SYNGAP1 count is at 209! Sign up or Update your Ciitizen Records - Sign-UP https://ciitizen.com/syngap1 - Sign-IN https://app.ciitizen.com/ iPSCs & Missense Mutations/Variants - https://syngap.fund/ipsc - https://www.syngapresearchfund.org/ips-cell-models - 30 lines, 3 missense on the list, 1 more in Europe I know about - I urge you to raise for cell lines if you are a missense. $4k for a line, $7k for an isogenic control, $11k to make sure a mutation has a chance to be studied. 30% risk on the first line. There is so much work to do, volunteer - Info@SyngapResearchFund.org This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts: https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 95 of #Syngap10 - February 28, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Rare Disease Day 2023 - Hattie Video, Coller & McKee Webinars, Missense SYNGAP1 iPSC, $20k, Apply for a Grant, Sprint4Syngap, Join us. #S10e95   It's RARE DISEASE DAY! Hattie has a new video! https://www.syngapresearchfund.org/families/movies    I'm off to DC for NIH Day and RD Advocacy with Everylife Foundation - https://ncats.nih.gov/news/events/rdd - https://everylifefoundation.org/rare-advocates/rare-disease-week/    We have a $20k match!  - https://syngap.fund/rdd23  - https://secure.givelively.org/donate/syngap-research-fund-incorporated/srf-rare-disease-day-2023   Deadline for Grants is 3/1 - https://www.syngapresearchfund.org/post/134-apply-for-syngap1-research-grants-by-march-1st-or-september-1st    #Sprint4Syngap - https://syngap.fund/sprint23  - Main page https://secure.givelively.org/donate/syngap-research-fund-incorporated/sprint4syngap-2023  - 15 Teams! Eight already raising funds: Team Tavilla, Emma Mae, Reef, Kai, Naya, Hope4Hadley, Teddy & Lizzy.  Seven more ready to go. - Remember, there is an adaptive bike in play! - New family has an event to go to… COMMUNITY   Amazing Webinars - Jeff Coller - mRNA - March 16th  https://www.syngapresearchfund.org/webinars/68-harnessing-messenger-rna-metabolism-for-the-development-of-precision-gene-therapy-syngap1  - Jillian McKee - April 27th - https://syngap.fund/mckee    Ciitizen SYNGAP1 count is at 209! Sign up or Update your Ciitizen Records - Sign-UP https://ciitizen.com/syngap1  - Sign-IN https://app.ciitizen.com/   iPSCs & Missense Mutations/Variants - https://syngap.fund/ipsc   - https://www.syngapresearchfund.org/ips-cell-models - 30 lines, 3 missense on the list, 1 more in Europe I know about - I urge you to raise for cell lines if you are a missense.  $4k for a line, $7k for an isogenic control, $11k to make sure a mutation has a chance to be studied.  30% risk on the first line.   There is so much work to do, volunteer - Info@SyngapResearchFund.org    This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts:  https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 95 of #Syngap10 - February 28,  2023  #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat

https://psychiatry.dev/wp-content/uploads/speaker/post-11999.mp3?cb=1677249729.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease – PubMed Yann Le Guen et al. Journal ofFull EntryAssociation of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease – PubMed

In this episode, Dr Jonathan Hudson discusses key points from a recent case report published in EHJ – Case Reports.

Missense Variants are Finally Getting Attention. Reclassification. Grants. #S10e66 #SyngapCensus for 2q22 is 1098! https://www.syngapresearchfund.org/post/syngapcensus-2022-update-43-in-q2-2022 Incidence and Prevalence Article https://www.syngapresearchfund.org/post/why-are-we-so-sure-that-syngap1-related-intellectual-disability-is-under-diagnosed GRANT TO COURTNEY LAB - Spread the word Twitter: https://twitter.com/JMGraglia/status/1544634675808722946 LinkedIn: https://www.linkedin.com/posts/curesyngap1_missense-collaboration-syngap1-activity-6950413553703030784-6VHG/ Facebook: https://www.facebook.com/cureSYNGAP1/posts/pfbid02JshtwTaK1eSPJ4kUy9Ga1ZrQGAyvk7DyrK1tPWk5UauYDx8mTY8ENeYCUfCnPwXEl Press Release: ​​https://www.eurekalert.org/news-releases/957967 GENETICS Missense: https://www.genome.gov/genetics-glossary/Missense-Mutation Protein Truncating: Nonsense: https://www.genome.gov/genetics-glossary/Nonsense-Mutation Frameshift: https://www.genome.gov/genetics-glossary/Frameshift-Mutation FUNDRAISERS - MICE: Help us Make 2! https://syngap.fund/2mice EVENTS September 12-14 in San Diego - https://globalgenes.org/event/rare-patient-advocacy-summit/ October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree December 1 in TN - Syngap Science Meeting - https://syngap.fund/treat This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts: https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 66 of #Syngap10 - July 6, 2022 #CareAboutRare #Ciitizen #Ambry #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

#SyngapCensus for 2q22 is 1098!  https://www.syngapresearchfund.org/post/syngapcensus-2022-update-43-in-q2-2022   Incidence and Prevalence Article https://www.syngapresearchfund.org/post/why-are-we-so-sure-that-syngap1-related-intellectual-disability-is-under-diagnosed    GRANT TO COURTNEY LAB - Spread the word -Twitter: https://twitter.com/JMGraglia/status/1544634675808722946  -LinkedIn: https://www.linkedin.com/posts/curesyngap1_missense-collaboration-syngap1-activity-6950413553703030784-6VHG/  -Facebook: https://www.facebook.com/cureSYNGAP1/posts/pfbid02JshtwTaK1eSPJ4kUy9Ga1ZrQGAyvk7DyrK1tPWk5UauYDx8mTY8ENeYCUfCnPwXEl  -Press Release: ​​https://www.eurekalert.org/news-releases/957967    GENETICS Missense: https://www.genome.gov/genetics-glossary/Missense-Mutation Protein Truncating: - Nonsense: https://www.genome.gov/genetics-glossary/Nonsense-Mutation  - Frameshift: https://www.genome.gov/genetics-glossary/Frameshift-Mutation  FUNDRAISERS - MICE: Help us Make 2!  https://syngap.fund/2mice EVENTS -September 12-14 in San Diego - https://globalgenes.org/event/rare-patient-advocacy-summit/  -October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala -October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap  -November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree -December 1 in TN - Syngap Science Meeting - https://syngap.fund/treat   This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://www.syngapresearchfund.org/syngap10-podcast  Apple podcasts: https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818    Episode 66 of #Syngap10 - July 6, 2022 #CareAboutRare #Ciitizen #Ambry #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration 

Old School Syngap10 - Lots of great content in 10 minutes. Fundraising. Blogs. Webinars. Patient stories. Ciitizen. IT ALL TAKES MONEY - Emily's Fundraiser #HopeForHadley https://secure.givelively.org/donate/syngap-research-fund-incorporated/hope-for-hadley - 2nd Annual Sprint for Syngap is coming April 30, 2022. WEBINARS - La intención comunicativa en SYNGAP1 el sábado 5 de febrero | 9am Miami / 3pm Madrid https://syngap.fund/intencion - An Introduction to Autism BrainNet Thursday, February 10 @ 9 am PT/12 pm ET https://syngap.fund/ABN - The use of milk exosomes to increase the expression of SYNGAP1 expression in SYNGAP1 mice March 3, 2022 @ 9am PT/12pm ET https://syngap.fund/zempleni BLOGS - Diapers: https://www.syngapresearchfund.org/post/diapers-pull-ups-for-older-kids-a-moms-experience - Missense: https://www.syngapresearchfund.org/post/syngap1-frequent-de-novo-missense-variant-alert-study-opportunity-for-p-gly344 - https://www.genome.gov/sites/default/files/tg/en/illustration/missense_mutation.jpg MUTATION STORIES - c.3583-6G>A Europe and East Coast, connected! - c.333del and c.490 C>T Facebook Groups - Data https://docs.google.com/spreadsheets/d/13dAPdXJnF-ST4lJnKrgxEJ_03e7shyXg7jwiqeXSR7c/edit?usp=sharing CIITIZEN - Privacy https://ciitizen.com/privacy - Sign up https://ciitizen.com/SYNGAP1 - Nobody does it better. EXTRA CREDIT - Gene Fixers was VERY GOOD. Here is the replay. This is worth a listen. www.clubhouse.com/room/m26dGYr4?utm_medium=ch_room_xerc&utm_campaign=RgMbPQTckJlMoxenxVxCiQ-38225 REMEMBER - Raise funds at https://syngap.fund/give - Subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://syngap.fund/10 if you want a direct link for Apple: https://syngap.fund/10a Episode 45 of #Syngap10 - January 28, 2022 #braindonation #specialneedsdiapers #missense #ciitizen #privacy #SYNGAP1 #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #Genetics --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Old School Syngap10 - Lots of great content in 10 minutes.  Fundraising. Blogs. Webinars. Patient stories. Ciitizen. IT ALL TAKES MONEY - Emily's Fundraiser #HopeForHadley https://secure.givelively.org/donate/syngap-research-fund-incorporated/hope-for-hadley - 2nd Annual Sprint for Syngap is coming April 30, 2022.  WEBINARS - La intención comunicativa en SYNGAP1 el sábado 5 de febrero | 9am Miami / 3pm Madrid https://syngap.fund/intencion - An Introduction to Autism BrainNet Thursday, February 10 @ 9 am PT/12 pm ET https://syngap.fund/ABN - The use of milk exosomes to increase the expression of SYNGAP1 expression in SYNGAP1 mice March 3, 2022 @ 9am PT/12pm ET https://syngap.fund/zempleni BLOGS - Diapers: https://www.syngapresearchfund.org/post/diapers-pull-ups-for-older-kids-a-moms-experience - Missense: https://www.syngapresearchfund.org/post/syngap1-frequent-de-novo-missense-variant-alert-study-opportunity-for-p-gly344    - https://www.genome.gov/sites/default/files/tg/en/illustration/missense_mutation.jpg MUTATION STORIES - c.3583-6G>A Europe and East Coast, connected! - c.333del and c.490 C>T Facebook Groups - Data https://docs.google.com/spreadsheets/d/13dAPdXJnF-ST4lJnKrgxEJ_03e7shyXg7jwiqeXSR7c/edit?usp=sharing  CIITIZEN  - Privacy https://ciitizen.com/privacy - Sign up https://ciitizen.com/SYNGAP1  - Nobody does it better. EXTRA CREDIT - Gene Fixers was VERY GOOD.  Here is the replay.  This is worth a listen. www.clubhouse.com/room/m26dGYr4?utm_medium=ch_room_xerc&utm_campaign=RgMbPQTckJlMoxenxVxCiQ-38225 REMEMBER - Raise funds at https://syngap.fund/give - Subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://syngap.fund/10 if you want a direct link for Apple: https://syngap.fund/10a  Episode 45 of #Syngap10 - January 28, 2022   #braindonation #specialneedsdiapers #missense #ciitizen #privacy #SYNGAP1 #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #Genetics

In this episode, Mike reflected on a conversations with and questions from SYNGAP parents who have responded to previous episodes of SYNGAP10. As usual, it was packed. Thanks to DISORDER for listing SYNGAP10 as one of the best Rare Disease podcasts. We are honored. https://www.rarediseasefilmfestival.com/rarediseasepodcasts Reflections on conversation with parents, especially the parents of Adult SynGAPians. We had a great webinar this week with Lori Unumb about ABA, Autism and Advocacy, you can view it on our webinars page https://www.syngapresearchfund.org/families/resources/webinars Next week we will have a great webinar with Prof. Haas of UBC about missense mutations. Don't miss it. https://www.syngapresearchfund.org/webinars/functional-assessment-of-missense-variants-of-syngap1-kurt-haas Ciitizen continues to grow, sign up at https://Ciitizen.com/SYNGAP1 Mike answered a great question about cost and access. Explaining why we are hopeful that payers will support our therapies. --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Yup...halfway through season 2 - and still no live Scrabble tournaments.  Meh!  Well why not study something a lil different today...the MID and MIS uncommon prefixes.  It's not like you're MIS-sing anything else to do yet....  | MIDAIRS  |  | MIDCULT  |  | MIDDENS  |  | MIDDIES  |  | MIDDLER  |  | MIDGUTS  |  | MIDIRON  |  | MIDLEGS  |  | MIDLINE  |  | MIDLIST  |  | MIDNOON  |  | MIDRASH  |  | MIDRIBS  |  | MIDSOLE  |  | MIDBRAIN  |  | MIDLIFER  |  | MIDMOSTS  |  | MIDSPACE  |  | MIDSTORY  |  | MIDWATCH  |  | MIDWATER  |  | MIDWIFED  | MIDWIVE MIDWIFED |   |  | MISAIMS  |  | MISALLY  |  | MISAVER  |  | MISBIAS  |  | MISBIND  |  | MISCITE  |  | MISCODE  |  | MISCOIN  |  | MISCOOK  |  | MISCUED  |  | MISDEEM  |  | MISCUTS  |  | MISDRAW  | MISDREW | MISEASE  |  | MISEATS  |  | MISEDIT  |  | MISFORM  |  | MISGAGE  | MISGAUGE | MISHITS  |  | MISJOIN  |  | MISKALS  |  | MISKICK  |  | MISKNOW  | MISNEW MISKNOWN` | MISLIES  |  | MISLIKE  |  | MISLIVE  |  | MISMOVE  |  | MISPAGE  |  | MISPART  |  | MISPENS  |  | MISPLAN  |  | MISPLED  |  | MISRATE  |  | MISRELY  |  | MISSALS  |  | MISSELS  |  | MISSETS  |  | MISSHOD  |  | MISTEUK  |  | MISTUNE  |  | MISWORD  |  | MISWRIT  |  | MISYOKE  |  | MISTBOW  |  | MISAGENT  |  | MISALTER  |  | MISBEGOT  |  | MISAWARD  |  | MISCIBLE  |  | MISENROL  |  | MISERERE  |  | MISEVENT  |  | MISFAITH  |  | MISFOCUS  |  | MISFRAME  |  | MISGIVES  |  | MISHMASH  | MISHMOSH | MISINFER  |  | MISINTER  |  | MISLABOR  |  | MISLAYER  |  | MISLIKER  |  | MISLODGE  |  | MISMATED  |  | MISOGAMY  |  | MISOGANY  |  | MISOLOGY  |  | MISPAINT  |  | MISPRIZE  |  | MISPOISE  |  | MISREFER  |  | MISSENSE  |  | MISSOUND  |  | MISSPELT  | MISSPELLED | MISSTAMP  |  | MISSTEER  |  | MISSTOPS  |  | MISSUITS  |  | MISTAKER  |  | MISTITLE  |  | MISTRACE  |  | MISTRYST  |  | MISTUTOR  |  | MISUNION  |  | MISUSERS  | 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.06.327825v1?rss=1 Authors: Xavier, B. M., Zein, A. A., Venes, A., Wang, J., Lee, J.-Y. Abstract: The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular framework was recently established by a crystal structure of human ABCG5/G8 and reveals a network of polar and charged amino acids in the core of the transmembrane domains, namely polar relay. In this study, we utilize genetic variants to dissect the mechanistic role of this transmembrane polar relay in controlling ABCG5/G8 function. We demonstrated a sterol-coupled ATPase activity of ABCG5/G8 by cholesteryl hemisuccinate (CHS), a relatively water-soluble cholesterol memetic, and characterized CHS-coupled ATP catalysis by using three loss-of-function missense variants, two sitosterolemia mutations (E146Q and R543S; within polar relay) and one sterol-binding mutation (A540F; distant from the polar relay). The results established an in vitro phenotype of the loss-of-function and missense mutations of ABCG5/G8, showing significantly impaired ATPase activity and loss of energy sufficient to weaken the polar relay network by all three mutants. Our data herein provide a biochemical evidence underlying the importance of the polar relay in regulating the catalytic activity of ABCG5/G8 sterol transporter. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.29.318683v1?rss=1 Authors: Sanchez-Lanzas, R., Castano, J. G. Abstract: DJ-1/PARK7 mutations are linked with familial forms of early onset Parkinson disease (PD). We have studied the degradation of untagged DJ-1 WT and missense mutants in mouse embryomic fibroblasts obtained from DJ-1 null mice, an approach closer to the situation in patients carrying homozygous mutations. The results showed that the mutants: L10P, M26I, A107P, P158DEL, L166P, E163K and L172Q are unstable proteins, while A39S, E64D, R98Q, A104T, D149A, A171S, K175E and A179T are as stable as the DJ-1 WT. Inhibition of proteasomal and autophagic-lysosomal pathways had little effect on their degradation. Immunofluorescence and biochemical fractionation studies indicated that M26I, A107P, P158DEL, L166P, E163K and L172Q mutants associate with mitochondria. Silencing of mitochondrial matrix protease LonP1 produced a strong reduction of the degradation of those mitochondrialy associated DJ-1 mutants, but not of mutant L10P. These results demonstrated a mitochondrial pathway of degradation of those DJ-1 missense mutants implicated in PD pathogenesis. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.12.241976v1?rss=1 Authors: Fadl, H. A. O., Abdelmoneim, A. H., Elbager, S. G. Abstract: ABSTRACT Background: CLL: Chronic lymphocytic leukemia is a chronic type of haematological malignancies that evoked from lymph proliferative origin of bone marrow and secondary lymphoid tissue, resultant in proliferation and progressive accumulation of distinct monoclonal CD5 /CD19 /CD23 B lymphocytes in the bone marrow, peripheral blood, and lymphatic organs. CD38 is a multifunctional ecto-enzyme, known to be a direct contributor in pathogenesis of CLL by poorly understood mechanism. Even though , it highly expressed in CLL. At specific position of CD38 gene sequence, substitution of single nucleotide may result in change in amino acid that ends by consequent alteration of protein structure. Aim: To study CD38 polymorphism and to predict its effect on structure and subsequently function of CD38 molecule. Methodology and Result: The bioinformatic analysis of CD38 gene had been carried out by using several soft wares. Functional analysis by SIFT,Polyphen2, and PROVEAN reveled 12 deleterious SNPs. These SNPs were further analyzed by SNAP2, SNP@GO. PMut, STRING and other soft wars. Furthermore, Stability analysis was done using I-Mutant and MUpro software where seven SNPs were found to decrease the stability of the protein by I-Mutant ,while two SNPs increase it. At the same time, eight SNPs were found to decrease the stability by Mupro software while only one SNP is predicted to increase it. Finally, Physiochemical analysis was done using Project Hope. Conclusion: In summary, CD38 genotype seems to have twelve SNP that possibly will result in deleterious effect on Protein Structure. This genetic variation eventually will lead to alteration in potential molecule functions .Which effect the progression of CLL By the end. Keywords: B-Chronic lymphocytic leukemia, missense single nucleotide polymorphism, and CD38 gene. Copy rights belong to original authors. Visit the link for more info

Point, Frame Shift, and Nonsense vs. Missense. Further divided Missense to Silent, Conservative, and Non-Conservative.

In this special episode # 71 co-presented with the SADS Foundation (SADS.ORG) we speak with the president of the foundation, Professor Michael Ackerman of The Mayo Clinic about a recent work he co-authored on a novel approach to assessing patients with possible CPVT. How should the phenotype help to inform genotype results? Can a novel CPVT scorecard help to improve our understanding of genetic test results? How are genes determined to be 'benign', 'likely disease causing' or a variant of uncertain significance (VUS)? We discuss these issues and more with Dr. Ackerman who provides great insights into this fascinating topic that affects all cardiologists who use genetic testing as part of their practice. doi: 10.1161/CIRCGEN.119.002510

In this special episode # 71 co-presented with the SADS Foundation (SADS.ORG) we speak with the president of the foundation, Professor Michael Ackerman of The Mayo Clinic about a recent work he co-authored on a novel approach to assessing patients with possible CPVT. How should the phenotype help to inform genotype results? Can a novel CPVT scorecard help to improve our understanding of genetic test results? How are genes determined to be 'benign', 'likely disease causing' or a variant of uncertain significance (VUS)? We discuss these issues and more with Dr. Ackerman who provides great insights into this fascinating topic that affects all cardiologists who use genetic testing as part of their practice. doi: 10.1161/CIRCGEN.119.002510

Commentary by Dr. Valentin Fuster

Abraham Acevedo Arozena, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire - UK speaks on "Missense mutations in mouse Tardbp differentially affect TDP43 functions - RNA Metabolism: Changing Paradigms in Neurodegeneration". This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Background Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. Methods We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 30 end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Background: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS. Methods and results: We investigated SOS1 in a large cohort of patients with disorders of the NS–CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene. Conclusion: We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gainof- function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.

The regulation of phosphate metabolism is a complex process that is still only partly understood. At the end of the eighties, studies in a mouse model for hypophosphatemic rickets provided evidence that phosphate wasting could not be explained by a primary defect of the kidney but rather by an unknown circulating factor with phosphaturic properties. X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and tumor induced osteomalacia (TIO) are three well defined human disorders of isolated renal phosphate wasting. XLH and ADHR are mendelian diseases while TIO is caused by rare, mostly benign tumors. The opposite phenotype, hyperphosphatemia due to increased renal phosphate reabsorption is associated to the recessive disorder familial tumoral calcinosis (FTC). At the beginning of this work the genes mutated in XLH and ADHR were cloned. One gene codes for the endopeptidase PHEX, the other for the fibroblast growth factor FGF23. Both proteins are probably involved in a novel common pathway of the regulation of phosphate homeostasis. Missense mutations in FGF23 causing phosphate wasting in patients with ADHR, overexpression of FGF23 in tumors from patients with TIO, and the observation that FGF23 plasma levels are elevated in most patients with XLH provided strong evidence that FGF23 is a hormone with phosphaturic activity. However, the function of FGF23 in the regulation of phosphate metabolism is far from understood. The intention of this study was to investigate the molecular properties of native FGF23 and its mutant forms. I conducted protein expression experiments in HEK293 cells which showed that native FGF23 is a secreted protein partially processed into an N-terminal fragment and a C-terminal fragment. I provided evidence that this cleavage occurs during protein secretion and it is performed by subtilisin like-proprotein convertases (SPCs). In addition, I determined that native FGF23 undergoes O-linked glycosylation before secretion by using a deglycosylation assay. Further, RT-PCR analysis of human tissues showed FGF23 expression in whole fetus, heart, liver, thyroid/parathyroid, small intestine, testis, skeletal muscle, differentiated chondrocytes and TIO tumor tissue. In mouse, FGF23 was expressed in day 17 embryo and spleen. The FGF23 ADHR mutations replace arginine residues at the SPC cleavage site (RXXR motif). By expression of the FGF23-R176Q and –R179Q mutant proteins in HEK293 cells I showed that ADHR mutations prevent cleavage at the RXXR site and stabilize FGF23. This alteration in the FGF23 cleavage enhances FGF23 phosphaturic activity in ADHR. Familial tumoral calcinosis (FTC) with hyperphosphatemia is a disease considered the mirror image of the hypophosphatemic condition. It is known that FTC is caused by mutations in the GALNT3 gene. By performing mutation analysis in two families with FTC, I could show that FTC can also be caused by inactivating mutations in the FGF23 gene. To characterize the FGF23-S71G mutant protein I conducted in vitro expression assays, immunocytochemistry and ELISA to measure the FGF23 plasma levels in the patient with FTC. Taken together the results of these experiments showed that intact FGF23-S71G mutant protein remained inside the cells and only the C-terminal FGF23 fragment was secreted. These investigations demonstrate that FGF23 mutations in ADHR and FTC have opposite effects on phosphate homeostasis. There is evidence that the endopeptidase PHEX which is mutated in patients with XLH and FGF23 act in the same pathway. PHEX function resides upstream of FGF23 and may be involved in the degradation of FGF23 thereby regulating its phosphaturic activity. I designed an assay with a recombinant secreted form of PHEX (secPHEX) to prove whether FGF23 is a substrate of PHEX. Although secPHEX activity could be demonstrated by degradation of PTHrP107-139, secPHEX failed to degrade FGF23 in this assay. These results provided evidence against a direct interaction of PHEX and FGF23.

Background: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984.Methods: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene.Results: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C).Conclusions: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.

Die X-chromosomal gebundene Adrenoleukodystrophie stellt eine vererbte Störung der peroxisomalen ß-Oxidation von Fettsäuren dar, die zu einer Akkumulation von überlangkettigen Fettsäuren in allen Körperflüssigkeiten führt. X-ALD wird durch Mutationen im ALD-Gen verursacht, welches ein peroxisomales Membranprotein aus der Superfamilie der ABCTransporter (ATP-binding cassette) kodiert. Die Erkrankung führt zu einer fortschreitenden Demyelinisierung des ZNS, einer peripheren Neuropathie sowie adrenokortikaler Insuffizienz. Es findet sich jedoch eine sehr hohe Variabilität phänotypischer Verlaufsformen. Aus bislang unklaren Gründen zeigt ein Großteil der heterozygoten Überträgerinnen - im Gegensatz zu der überwiegenden Mehrzahl anderer X-chromosomal vererbter Erkrankungen - sowohl die biochemischen als auch die klinischen Merkmale einer X-ALD in abgemilderter Form. Zur Erklärung dieses Phänomens sollte die Untersuchung der X-Inaktivierung heterozygoter Überträgerinnen beitragen, da in der Vergangenheit postuliert wurde, daß eine zugunsten des mutierten ALD-Allels verschobene X-Inaktivierung (mit-)verantwortlich sei für das Auftreten erhöhter Konzentrationen überlangkettiger Fettsäuren und neurologischer Symptome bei ALDÜberträgerinnen. Zur Untersuchung der X-Inaktivierung wurde der hochinformative Androgenrezeptor-Test etabliert und in einigen Punkten modifiziert und verbessert. Das Testprinzip beruht auf der PCRAmplifikation eines hochpolymorphen CAG-Repeats im Exon 1 des Androgenrezeptor-Gens nach einer Inkubation von genomischer DNA mit methylierungssensitiven Restriktionsenzymen. Die Verwendung eines fluoreszenz-markierten Primers in der PCR ermöglichte eine präzise automatisierte Auswertung mittels Fragmentanalyse. Neben einer Bestimmung der überlangkettigen Fettsäuren im Plasma wurde der Heterozygotenstatus der ALD-Überträgerinnen durch eine Mutationsanalyse des ALD-Gens eindeutig belegt. Dabei konnten in allen 15 untersuchten Familien Mutationen im ALD-Gen identifiziert werden. Bei 8 Familien fanden sich neue, bislang unveröffentlichte Mutationen. Das Mutationsspektrum umfaßte 10 Missense- (67 %), zwei Nonsense- (13 %), zwei Splice-Site- Mutationen (13 %) und eine Frameshift-Mutation (6 %). Die X-Inaktivierungsmuster in Leukozyten heterozygoter ALD-Überträgerinnen wurden erstmals im Vergleich zu einem verwandten und einem nicht-verwandten Kontrollkollektiv untersucht. Bei 7 von 22 Überträgerinnen (32 %) zeigte sich eine ausgeprägte Verschiebung der X-Inaktivierung (Skewing) zugunsten eines Allels (> 80:100). Im Gegensatz dazu war ein ausgeprägtes Skewing weder bei den Nicht-Überträgerinnen aus ALD-Familien noch bei den Kontrollen zu beobachten. In diesen Gruppen fanden sich nur random X-Inaktivierung und mildes Skewing zu annähernd gleichen Teilen. Bei beiden Gruppen glich die Verteilung der XInaktivierungsmuster einer Gauss’schen Normalverteilungskurve. Die Unterschiede zwischen ALD-Überträgerinnen und unverwandtem Kontrollkollektiv erwiesen sich als statistisch hochsignifikant. Eine Korrelation zwischen dem Grad der X-Inaktivierung in Leukozyten heterozygoter ALDÜberträgerinnen und deren biochemischen Parametern (Konzentration überlangkettiger Fettsäuren im Plasma) war nicht nachweisbar. Unsere Daten belegen, daß das häufige Auftreten einer Verschiebung der X-Inaktivierung zugunsten eines Allels bei ALD-Überträgerinnen mit dem mutierten ALD-Allel in Zusammenhang steht und wahrscheinlich durch Selektionsmechanismen verursacht wird. Diese Selektionsmechanismen wirken nach dem primären X-Inaktivierungsprozeß. Andere sekundäre Einflußvariablen wie Alter oder genetische Faktoren des X-Inaktivierungsprozesses selbst wurden mit hoher Wahrscheinlichkeit ausgeschlossen. Anhand von Transkriptanalysen in kultivierten Fibroblasten konnte darüberhinaus gezeigt werden, daß einerseits eine Selektion zugunsten des Wildtyp-Allels, andererseits jedoch auch eine Selektion zugunsten des mutierten Allels vorkommt. Der bislang in der Literatur postulierte Selektionsvorteil des mutierten ALD-Allels wird somit in Frage gestellt.

Etwa 10 % der gesamten Erkrankungsfälle der humanen TSEs werden durch die Gruppe der vererbbaren Formen dieser Krankheiten repräsentiert, für die bislang in allen untersuchten Fällen Punktmutationen oder Insertionen im Prionprotein-Gen des Menschen (PRNP) nachgewiesen werden konnten. Obwohl bereits mehr als 20 TSE-assoziierte Mutationen in PRNP beschrieben wurden, ist nach wie vor relativ wenig über die Zellbiologie, d. h. den zellulären Transport bzw. die zelluläre Lokalisation dieser PrPMutanten bekannt. Aus diesem Grund wurde erstmalig ein Modellsystem mit homologen Maus-PrPs in der vielfach eingesetzten Maus-Neuroblastom-Zelllinie N2a etabliert, welches durch die Verwendung des grünen Fluoreszenzproteins (GFP) als integrales Markerprotein in PrP eine direkte Beobachtung von PrP und PrP-Mutanten in lebenden Zellen ermöglichte. Es wurden insgesamt neben der Chimäre mit wt PrP und GFP weitere 14 Chimären hergestellt, von denen 11 mit PrP-Mutanten humaner, vererbbarer Prionkrankheiten korrespondierten. Die Ausweitung des Modellsystems auf die PrPMutanten wurde erst nach einer sorgfältigen Überprüfung der Chimäre mit wt PrP (GFPwtPrP) vorgenommen, die zeigte, dass sich GFP-wtPrP in allen untersuchten Parametern wie natives PrP verhielt. Für die 11 TSE-assoziierten PrP-Mutanten konnten drei zelluläre Phänotypen identifiziert werden, die sich deutlich voneinander unterschieden. So konnte für bestimmte Missense- und Insert-Mutanten ein sekretorischer Transport wie bei der Wildtyp-Kontrolle festgestellt werden, mit einer Lokalisation der Proteine im Golgi- Apparat und auf der Zelloberfläche. Dem entgegen zeigten die zwei bislang beschriebenen, TSE-assoziierten Nonsense-Mutanten keinen Transport entlang eines sekretorischen Weges, sondern eine Lokalisation im Cytoplasma und im Zellkern. Als dritter Phänotyp konnte auf Grund einer Blockierung des sekretorischen Transports im Golgi-Apparat eine intrazelluläre Akkumulation im ER/Golgi sowohl für eine Missense-Mutante, deren Mutation zu einer Zerstörung des Sequenzmotivs für eine N-Glykosylierung führte als auch für eine Insert-Mutante, welche die bislang größte Insertion von zusätzlichen 9 Kopien eines Oktapeptids aufwies, detektiert werden. Die mittels des Modellsystems identifizierten, unterschiedlichen Lokalisationen der PrPMutanten deuten darauf hin, dass die familiären Prionkrankheiten nicht einer einheitlichen, zellulären Aberration unterliegen, sondern höchstwahrscheinlich entlang mehrerer zytopathogener Routen ausgebildet werden.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.19.048819v1?rss=1 Authors: Prieto, M., Folci, A., Poupon, G., Schiavi, S., Buzzelli, V., Francois, U., Pousinha, P., Lattuada, N., Abelanet, S., Pronot, M., Castagnola, S., Chafai, M., Khayachi, A., Brau, F., Deval, E., Francolini, M., Bardoni, B., Humeau, Y., Trezza, V., Martin, S. Abstract: Copy rights belong to original authors. Visit the link for more info