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The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype

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Item Type:Article
Title:The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype
Creators Name:Yigit, G. and Saida, K. and DeMarzo, D. and Miyake, N. and Fujita, A. and Yang Tan, T. and White, S.M. and Wadley, A. and Toliat, M.R. and Motameny, S. and Franitza, M. and Stutterd, C.A. and Chong, P.F. and Kira, R. and Sengoku, T. and Ogata, K. and Guillen Sacoto, M.J. and Fresen, C. and Beck, B.B. and Nürnberg, P. and Dieterich, C. and Wollnik, B. and Matsumoto, N. and Altmüller, J.
Abstract:RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.
Keywords:hemihypotrophy, Postzygotic Mutations, RHOA, Skin Hypopigmentation, Small GTPases
Source:Human Mutation
Page Range:591-599
Date:March 2020
Official Publication:https://doi.org/10.1002/humu.23964
PubMed:View item in PubMed

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