TY - JOUR
T1 - A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome
AU - Bustos, Francisco
AU - Espejo-Serrano, Carmen
AU - Segarra-Fas, Anna
AU - Toth, Rachel
AU - Eaton, Alison J.
AU - Kernohan, Kristin D.
AU - Wilson, Meredith J.
AU - Riley, Lisa G.
AU - Findlay, Greg M.
N1 - We thank the protein production team in MRC-PPU reagents and services for recombinant protein production and Prof Miratul Muqit (MRC-PPU, University of Dundee) for critical reading of the manuscript. F.B. and G.M.F are supported by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship (211209/Z/18/Z) and a Medical Research Council New Investigator Research Grant (MR/N000609/1). C.E-S. is supported by a Wellcome Trust PhD studentship and A.S-F. by a MRC-PPU prize studentship. Part of this work was performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation (A.J.E., K.D.K.). Part of this work performed under the Rare Diseases Functional Genomics programme, supported by the Luminesce Alliance – Innovation for Children’s Health, a not for profit cooperative joint venture between the Sydney Children’s Hospitals Network, the Children’s Medical Research Institute, and the Children’s Cancer Institute. It has been established with the support of the NSW Government to coordinate and integrate pediatric research. Luminesce Alliance is also affiliated with the University of Sydney and the University of New South Wales Sydney (M.J.W. and L.G.R)
PY - 2021/5/5
Y1 - 2021/5/5
N2 - Tonne-Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome associated with variable clinical features including craniofacial abnormalities, hypogenitalism and diaphragmatic hernia. TOKAS is caused exclusively by variants in the gene encoding the E3 ubiquitin ligase gene RLIM, also known as RNF12. Here we report identification of a novel RLIM missense variant, c.1262A>G p.(Tyr421Cys) adjacent to the regulatory basic region, which causes a severe form of TOKAS resulting in perinatal lethality by diaphragmatic hernia. Inheritance and X-chromosome inactivation patterns implicate RLIM p.(Tyr421Cys) as the likely pathogenic variant in the affected individual and within the kindred. We show that the RLIM p.(Tyr421Cys) variant disrupts both expression and function of the protein in an embryonic stem cell model. RLIM p.(Tyr421Cys) is correctly localised to the nucleus, but is readily degraded by the proteasome. The RLIM p.(Tyr421Cys) variant also displays significantly impaired E3 ubiquitin ligase activity, which interferes with RLIM function in Xist long-non-coding RNA induction that initiates imprinted X-chromosome inactivation. Our data uncover a highly disruptive missense variant in RLIM that causes a severe form of TOKAS, thereby expanding our understanding of the molecular and phenotypic spectrum of disease severity.
AB - Tonne-Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome associated with variable clinical features including craniofacial abnormalities, hypogenitalism and diaphragmatic hernia. TOKAS is caused exclusively by variants in the gene encoding the E3 ubiquitin ligase gene RLIM, also known as RNF12. Here we report identification of a novel RLIM missense variant, c.1262A>G p.(Tyr421Cys) adjacent to the regulatory basic region, which causes a severe form of TOKAS resulting in perinatal lethality by diaphragmatic hernia. Inheritance and X-chromosome inactivation patterns implicate RLIM p.(Tyr421Cys) as the likely pathogenic variant in the affected individual and within the kindred. We show that the RLIM p.(Tyr421Cys) variant disrupts both expression and function of the protein in an embryonic stem cell model. RLIM p.(Tyr421Cys) is correctly localised to the nucleus, but is readily degraded by the proteasome. The RLIM p.(Tyr421Cys) variant also displays significantly impaired E3 ubiquitin ligase activity, which interferes with RLIM function in Xist long-non-coding RNA induction that initiates imprinted X-chromosome inactivation. Our data uncover a highly disruptive missense variant in RLIM that causes a severe form of TOKAS, thereby expanding our understanding of the molecular and phenotypic spectrum of disease severity.
UR - https://www.biorxiv.org/content/10.1101/2020.12.09.417873v1
UR - http://www.scopus.com/inward/record.url?scp=85105386729&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-88911-3
DO - 10.1038/s41598-021-88911-3
M3 - Article
C2 - 33953269
VL - 11
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 9560
ER -