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Holtz, A.M.* ; Vancoil, R.* ; Vansickle, E.A.* ; Carere, D.A.* ; Withrow, K.* ; Torti, E.* ; Juusola, J.* ; Millan, F.* ; Person, R.* ; Guillen Sacoto, M.J.* ; Si, Y.* ; Wentzensen, I.M.* ; Pugh, J.* ; Vasileiou, G.* ; Rieger, M.* ; Reis, A.* ; Argilli, E.* ; Sherr, E.H.* ; Aldinger, K.A.* ; Dobyns, W.B.* ; Brunet, T. ; Hoefele, J.* ; Wagner, M. ; Haber, B.* ; Kotzaeridou, U.* ; Keren, B.* ; Heron, D.* ; Mignot, C.* ; Heide, S.* ; Courtin, T.* ; Buratti, J.* ; Murugasen, S.* ; Donald, K.A.* ; O'Heir, E.* ; Moody, S.* ; Kim, K.H.* ; Burton, B.K.* ; Yoon, G.* ; Campo, M.d.* ; Masser-Frye, D.* ; Kozenko, M.* ; Parkinson, C.* ; Sell, S.L.* ; Gordon, P.L.* ; Prokop, J.W.* ; Karaa, A.* ; Bupp, C.* ; Raby, B.A.*

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

Genet. Med. 24, 2065-2078 (2022)
Postprint DOI PMC
Open Access Green
Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. Methods: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. Results: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. Conclusion: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hedgehog Signaling ; Myh10 ; Neurodevelopmental Disorder ; Nonmuscle Myosin ; Primary Cilia
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Quellenangaben Volume: 24, Issue: 10, Pages: 2065-2078 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503292-001
G-503200-001
Grants Simons Foundation Autism Research Initiative
Broad Institute
National Eye Institute
National Human Genome Research Institute
National Heart, Lung, and Blood Institute
National Institute of Mental Health
National Institutes of Health
Harvard Center for Mendelian Genomics
DOI 10.1016/j.gim.2022.07.005
WOS ID WOS:000879580900008
Scopus ID 85136155715
PubMed ID 35980381
Erfassungsdatum 2022-11-14
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