An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Mah-Som Annelise Y, Daw Jil, Huynh Diana, Wu Mengcheng, Creekmore Benjamin C, Burns William, Skinner Steven A, Holla Øystein L, Smeland Marie F, Planes Marc, Uguen Kevin, Redon Sylvia, Bierhals Tatjana, Scholz Tasja, Denecke Jonas, Mensah Martin A, Sczakiel Henrike L, Tichy Heidelis, Verheyen Sarah, Blatterer Jasmin, Schreiner Elisabeth, Thies Jenny, Lam Christina, Spaeth Christine G, Pena Loren, Ramsey Keri, Narayanan Vinodh, Seaver Laurie H, Rodriguez Diana, Afenjar Alexandra, Burglen Lydie, Lee Edward B, Chou Tsui-Fen, Weihl Conrad C, Shinawi Marwan S
Аннотация
Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.