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

  • Yiyao Chen 1,3,4 ,
  • Bingxin Yang 3,4 ,
  • Xiaoyu Merlin Zhang 5 ,
  • Songchang Chen 2,3 ,
  • Minhui Wang 6 ,
  • Liya Hu 7 ,
  • Nina Pan 3 ,
  • Shuyuan Li 3,4 ,
  • Weihui Shi 2 ,
  • Zhenhua Yang 5,10 ,
  • Li Wang 3,4 ,
  • Yajing Tan 3,4 ,
  • Jian Wang 3,4 ,
  • Yanlin Wang 3,4 ,
  • Qinghe Xing 1,8 ,
  • Zhonghua Ma 6 ,
  • Jinsong Li 5,9,10 ,
  • He-Feng Huang , 2,4,11 ,
  • Jinglan Zhang , 2,3,4 ,
  • Chenming Xu , 2,3
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  • 1. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
  • 2. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China
  • 3. International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
  • 4. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China
  • 5. 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
  • 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, TX 77030, USA
  • 8. Children’s hospital of Fudan University, Shanghai 201102, China
  • 9. School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
  • 10. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, Zhejiang, China
  • 11. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai 200011, China
huanghefg@hotmail.com
jinglanzhang@foxmail.com
chenming_xu2006@163.com

Received date: 28 Dec 2022

Accepted date: 29 Apr 2023

Copyright

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

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 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 (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 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 (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.

Cite this article

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 . Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement[J]. Protein & Cell, 2024 , 15(1) : 52 -68 . DOI: 10.1093/procel/pwad034

1
Agafonov DE, Kastner B, Dybkov O et al. Molecular architecture of the human U4/U6.U5 tri-snRNP. Science 2016;351:1416–1420.

DOI

2
Aksentijevich I, Schnappauf O. Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases. Nat Rev Rheumatol 2021;17:405–425.

DOI

3
Albers CA, Paul DS, Schulze H et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 2012;44:435–S2.

DOI

4
Askeland RB, Hannigan LJ, Ask H et al. Early manifestations of genetic risk for neurodevelopmental disorders. J Child Psychol Psychiatry 2022;63:810–819.

DOI

5
Au PYB, Goedhart C, Ferguson M et al. Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature. Eur J Human Genet 2018;26:1272–1281.

DOI

6
Benkirane M, Marelli C, Guissart C et al. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. Genet Med 2021;23:2160–2170.

DOI

7
Boesler C, Rigo N, Anokhina MM et al. A spliceosome inter-mediate with loosely associated tri-snRNP accumulates in the absence of Prp28 ATPase activity. Nat Commun 2016;7:11997.

DOI

8
Bomsztyk K, Denisenko O, Ostrowski J. hnRNP K: one protein multiple processes. BioEssays 2004;26:629–638.

DOI

9
Cehajic-Kapetanovic J, McClements ME, Whitfield J et al. Association of a novel intronic variant in RPGR With hypomorphic phenotype of X-linked retinitis pigmentosa. JAMA Ophthalmol 2020;138:1151–1158.

DOI

10
Charenton C, Wilkinson ME, Nagai K. Mechanism of 5′ splice site transfer for human spliceosome activation. Science (New York, N.Y.) 2019;364:362–367.

DOI

11
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics (Oxford, England) 2015;31:2745–2747.

DOI

12
Choufani S, McNiven V, Cytrynbaum C et al. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. Am J Hum Genet 2022;109:1867–1884.

DOI

13
Cingolani P, Platts A, Wang LL et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 2012;6:80–92.

DOI

14
Ciuzan O, Hancock J, Pamfil D et al. The evolutionarily conserved multifunctional glycine-rich RNA-binding proteins play key roles in development and stress adaptation. Physiol Plant 2015;153:1–11.

DOI

15
Consortium G. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science (New York, N.Y.) 2020;369:1318–1330.

16
Corley M, Burns MC, Yeo GW. How RNA-binding proteins interact with RNA: molecules and mechanisms. Mol Cell 2020;78:9–29.

DOI

17
DePristo MA, Banks E, Poplin R et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011;43:491–498.

DOI

18
Fernandez-Marmiesse A, Gouveia S, Couce ML. NGS technologies as a turning point in rare disease research, diagnosis and treatment. Curr Med Chem 2018;25:404–432.

DOI

19
Fishilevich S, Zimmerman S, Kohn A et al. Genic insights from integrated human proteomics in GeneCards. Database 2016;2016:baw030.

DOI

20
Fukuda T, Naiki T, Saito M et al. hnRNP K interacts with RNA binding motif protein 42 and functions in the maintenance of cellular ATP level during stress conditions. Genes Cells 2009;14:113–128.

DOI

21
Gebauer F, Schwarzl T, Valcárcel J et al. RNA-binding proteins in human genetic disease. Nat Rev Genet 2021;22:185–198.

DOI

22
Inoue A. RBM10: structure, functions, and associated diseases. Gene 2021;783:145463.

DOI

23
Iwanaga K, Sueoka N, Sato A et al. Heterogeneous nuclear ribonucleoprotein B1 protein impairs DNA repair mediated through the inhibition of DNA-dependent protein kinase activity. Biochem Biophys Res Commun 2005;333:888–895.

DOI

24
Johnston JJ, Teer JK, Cherukuri PF et al. NIH Intramural Sequencing Center (NISC). Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. Am J Hum Genet 2010;86:743–748.

DOI

25
Jumper J, Evans R, Pritzel A et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021;596:583–589.

DOI

26
Kaeppler KE, Stetson RC, Lanpher BC et al. Infant male with TARP syndrome: review of clinical features, prognosis, and commonalities with previously reported patients. Am J Med Genet A 2018;176:2911–2914.

DOI

27
Karczewski KJ, Francioli LC, Tiao G et al. Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–443.

DOI

28
Kleefstra T, Kramer JM, Neveling K et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet 2012;91:73–82.

DOI

29
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–1081.

DOI

30
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England) 2009;25:1754–1760.

DOI

31
Li J, Shi L, Zhang K et al. VarCards: an integrated genetic and clinical database for coding variants in the human genome. Nucleic Acids Res 2018;46:D1039–D1048.

DOI

32
Li Z, Guo Q, Zhang J et al. The RNA-Binding Motif protein family in cancer: friend or foe? Front Oncol 2021;11:757135.

DOI

33
Lutskiy MI, Sasahara Y, Kenney DM et al. Wiskott-Aldrich syndrome in a female. Blood 2002;100:2763–2768.

DOI

34
Ma S, Meng Z, Chen R et al. The Hippo Pathway: biology and pathophysiology. Annu Rev Biochem 2019;88:577–604.

DOI

35
McKenna A, Hanna M, Banks E et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297–1303.

DOI

36
McSweeney C, Dong F, Chen M et al. Full function of exon junction complex factor, Rbm8a, is critical for interneuron development. Transl Psychiatry 2020;10:379.

DOI

37
Moran-Jones K, Wayman L, Kennedy DD et al. hnRNP A2, a potential ssDNA/RNA molecular adapter at the telomere. Nucleic Acids Res 2005;33:486–496.

DOI

38
Niemi MEK, Martin HC, Rice DL et al. Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature 2018;562:268–271.

DOI

39
Parenti I, Rabaneda LG, Schoen H et al. Neurodevelopmental disorders: from genetics to functional pathways. Trends Neurosci 2020;43:608–621.

DOI

40
Proctor RH, Hohn TM, McCormick SP. Reduced virulence of Gibberella zeae caused by disruption of a trichothecene toxin biosynthetic gene. Mol Plant Microbe Interact 1995;8:593–601.

DOI

41
Quinlan AR. BEDTools: The Swiss-Army Tool for genome feature analysis. Curr Protoc Bioinformatics 2014;47:11.12.11-34.

DOI

42
Savatt JM, Myers SM. Genetic testing in neurodevelopmental disorders. Front Pediatr 2021;9:526779.

DOI

43
Schmidt C, Grønborg M, Deckert J et al. Mass spectrometry- based relative quantification of proteins in precatalytic and catalytically active spliceosomes by metabolic labeling (SILAC), chemical labeling (iTRAQ), and labelfree spectral count. RNA 2014;20:406–420.

DOI

44
Schneeberger PE, Kortüm F, Korenke GC et al. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder. Brain 2020;143:2437–2453.

DOI

45
Schwarz JM, Rödelsperger C, Schuelke M et al. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575–576.

DOI

46
Shankar SP, Grimsrud K, Lanoue L et al. A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder. Genet Med 2022;24:1567–1582.

DOI

47
Skórka A, Bielicka-Cymermann J, Gieruszczak-Białek D et al. Thrombocytopenia-absent radius (tar) syndrome: a case with agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney. Genet Couns (Geneva, Switzerland) 2005;16:377–382.

48
Soden SE, Saunders CJ, Willig LK et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 2014;6:265ra168.

DOI

49
Sutherland LC, Rintala-Maki ND, White RD et al. RNA binding motif (RBM) proteins: a novel family of apoptosis modulators? J Cell Biochem 2005;94:5–24.

DOI

50
Suvorova ES, Croken M, Kratzer S et al. Discovery of a splicing regulator required for cell cycle progression. PLoS Genet 2013;9:e1003305.

DOI

51
Tărlungeanu DC, Novarino G. Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Exp Mol Med 2018;50:1–7.

DOI

52
Untergasser A, Cutcutache I, Koressaar T et al. Primer3—new capabilities and interfaces. Nucleic Acids Res 2012;40:e115.

DOI

53
Wang M, Ma T, Wang H et al. The RNA binding protein FgRbp1 regulates specific pre-mRNA splicing via interacting with U2AF23 in Fusarium. Nat Commun 2021;12:2661.

DOI

54
Wongkittichote P, Choi T-I, Kim O-H et al. Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: a novel hypomorphic variant and high prevalence of tethered cord. Clin Genet 2023;103:167–178.

DOI

55
Wright CF, McRae JF, Clayton S et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet Med 2018;20:1216–1223.

DOI

56
Yang H, Wang K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc 2015;10:1556–1566.

DOI

57
Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 2005;280:1457–1464.

DOI

58
Zheng Y, Pan D. The Hippo Signaling Pathway in development and disease. Dev Cell 2019;50: 264–282.

DOI

59
Zweier C, Peippo MM, Hoyer J et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 2007;80:994–1001.

DOI

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