2. Academic Validation
  3. Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

  • Protein Cell. 2023 Jun 9;pwad034. doi: 10.1093/procel/pwad034.
Yiyao Chen 1 2 3,  Bingxin Yang 2 3,  Xiaoyu Merlin Zhang 4,  Songchang Chen 5 2,  Minhui Wang 6,  Liya Hu 7,  Nina Pan 2,  Shuyuan Li 2 3,  Weihui Shi 5,  Zhenhua Yang 4 8,  Li Wang 2 3,  Yajing Tan 2 3,  Jian Wang 2 3,  Yanlin Wang 2 3,  Qinghe Xing 1 9,  Zhonghua Ma 6,  Jinsong Li 4 10 8 11,  He-Feng Huang 5 3 12,  Jinglan Zhang 5 2 3,  Chenming Xu 5 2
Affiliations

Affiliations

  • 1 Institutes of Biomedical Science, Fudan University, Shanghai 200433, China.
  • 2 International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 3 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China.
  • 4 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai 200031, China.
  • 5 Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200433, China.
  • 6 State Key Laboratory of Rice Biology, the Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China.
  • 7 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States.
  • 8 School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
  • 9 Children's hospital of Fudan University, Shanghai 200433, China.
  • 10 Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 210031, China.
  • 11 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310124, China.
  • 12 Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China.
PMID: 37294900 DOI: 10.1093/procel/pwad034
Abstract

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with bi-allelic loss-of-function variants in the RBM42 gene. The patient is a two-year-old female with severe central nervous system abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant Animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing. Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global alternative splicing to abnormal embryonic development.

Figures
Products