首页|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

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Here,we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene.The patient is a 2-year-old female with severe central nervous system(CNS)abnormalities,hypotonia,hearing loss,congenital heart defects,and dysmorphic facial features.Familial whole-exome sequencing(WES)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 pro-tein stability in vivo.Additionally,p.A438T disrupts the interaction of RBM42 with hnRNP K,which is the causa-tive 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(WT)human RBM42.A mouse model carrying Rbm42 compound heterozygous variants,c.280C＞T(p.Q94*)and c.1306_1308delinsACA(p.A436T),demonstrated gross fetal develop-mental 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(AS).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 AS to abnormal embryonic development.

RBM42 geneRNA-binding proteinneurodevelopmental disorderAu-Kline syndromealternative splicing

Yiyao Chen、Bingxin Yang、Xiaoyu Merlin Zhang、Songchang Chen、Minhui Wang、Liya Hu、Nina Pan、Shuyuan Li、Weihui Shi、Zhenhua Yang、Li Wang、Yajing Tan、Jian Wang、Yanlin Wang、Qinghe Xing、Zhonghua Ma、Jinsong Li、He-Feng Huang、Jinglan Zhang、Chenming Xu

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Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China

International Peace Maternity and Child Health Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200030,China

Shanghai Key Laboratory of Embryo Original Diseases,Shanghai 200030,China

State Key Laboratory of Cell Biology,Shanghai Key Laboratory of Molecular Andrology,Shanghai Institute of Biochemistry and Cell Biology,CAS Center for Excellence in Molecular Cell Science,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China

Obstetrics and Gynecology Hospital,Institute of Reproduction and Development,Fudan University,Shanghai 200011,China

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

Verna and Marrs McLean Department of Biochemistry and Molecular Biology,Baylor College of Medicine,Houston,TX 77030,USA

School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,Zhejiang,China

Children's hospital of Fudan University,Shanghai 201102,China

School of Life Science and Technology,Shanghai Tech University,Shanghai 201210,China

Research Units of Embryo Original Diseases,Chinese Academy of Medical Sciences(No.2019RU056),Shanghai 200011,China

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National Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaScience and Technology Commission of Shanghai MunicipalityScience and Technology Commission of Shanghai MunicipalityScience and Technology Commission of Shanghai MunicipalityScience and Technology Commission of Shanghai MunicipalityCAMS Innovation Fund for Medical SciencesShanghai Municipal Commission of Health and family planningShanghai Municipal Commission of Health and family planningCollaborative Innovation Program of Shanghai Municipal Health CommissionClinical Research Plan of SHDCShanghai Clinical Research Center for Gynecological DiseasesShanghai Urogenital System Diseases Research CenterShanghai Frontiers Science Research Center of Reproduction and Development

2020YFA08040002021YFC27010022022YFC2703702819713448190149582071661821716778208810282192864822718981741197290023ZR140800021Y2190100222S319015002019-I2M-5-06420214011020215Y02162020CXJQ01SHDC2020CR1008A22MC19402002022ZZ01012

2024

10.1093/procel/pwad034

蛋白质与细胞

蛋白质与细胞

CSTPCD
影响因子：0.645
ISSN：
年,卷(期)：2024.15(1)
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