Yigit, Goekhan, Saida, Ken, DeMarzo, Danielle, Miyake, Noriko, Fujita, Atsushi, Yang Tan, Tiong, White, Susan M., Wadley, Alexandrea, Toliat, Mohammad R., Motameny, Susanne, Franitza, Marek, Stutterd, Chloe A., Chong, Pin F., Kira, Ryutaro ORCID: 0000-0002-6878-5081, Sengoku, Toru ORCID: 0000-0001-9461-8714, Ogata, Kazuhiro, Guillen Sacoto, Maria J., Fresen, Christine, Beck, Bodo B., Nuernberg, Peter, Dieterich, Christoph, Wollnik, Bernd, Matsumoto, Naomichi and Altmueller, Janine (2020). The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype. Hum. Mutat., 41 (3). S. 591 - 600. HOBOKEN: WILEY. ISSN 1098-1004

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saida, KenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeMarzo, DanielleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miyake, NorikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fujita, AtsushiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang Tan, TiongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wadley, AlexandreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franitza, MarekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stutterd, Chloe A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chong, Pin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kira, RyutaroUNSPECIFIEDorcid.org/0000-0002-6878-5081UNSPECIFIED
Sengoku, ToruUNSPECIFIEDorcid.org/0000-0001-9461-8714UNSPECIFIED
Ogata, KazuhiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guillen Sacoto, Maria J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fresen, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieterich, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matsumoto, NaomichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-123997
DOI: 10.1002/humu.23964
Journal or Publication Title: Hum. Mutat.
Volume: 41
Number: 3
Page Range: S. 591 - 600
Date: 2020
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIN STRESS FIBERS; PROTEIN-KINASE; CDC42 GTPASES; MUTATION; DETERMINES; ACTIVATION; DISCOVERY; CANCER; DOMAIN; RAC1Multiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12399

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