Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Mah-Som, AY; Daw, J; Huynh, D; Wu, M; Creekmore, BC; Burns, W; Skinner, SA; Holla, ØL; Smeland, MF; Planes, M; Uguen, K; Redon, S; Bierhals, T; Scholz, T; Denecke, J; Mensah, MA; Sczakiel, HL; Tichy, H; Verheyen, S; Blatterer, J; Schreiner, E; Thies, J; Lam, C; Spaeth, CG; Pena, L; Ramsey, K; Narayanan, V; Seaver, LH; Rodriguez, D; Afenjar, A; Burglen, L; Lee, EB; Chou, TF; Weihl, CC; Shinawi, MS.
An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.
Am J Hum Genet. 2023; 110(11): 1959-1975.
Doi: 10.1016/j.ajhg.2023.10.007
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- Co-Autor*innen der Med Uni Graz
- Blatterer Jasmin
- Schreiner Elisabeth
- Tichy Heidelis Anna
- Verheyen Sarah
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult - administration & dosage
- Humans - administration & dosage
- Valosin Containing Protein - genetics
- Muscular Diseases - administration & dosage
- Muscle Hypotonia - administration & dosage
- Mutation, Missense - genetics
- Neurodevelopmental Disorders - administration & dosage