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Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

ABSTRACT: The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

SUBMITTER: Martin EMMA

PROVIDER: S-EPMC7823106 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

Martin Ella M M A EMMA Enriquez Annabelle A Sparrow Duncan B DB Humphreys David T DT McInerney-Leo Aideen M AM Leo Paul J PJ Duncan Emma L EL Iyer Kavitha R KR Greasby Joelene A JA Ip Eddie E Giannoulatou Eleni E Sheng Delicia D Wohler Elizabeth E Dimartino Clémantine C Amiel Jeanne J Capri Yline Y Lehalle Daphné D Mory Adi A Wilnai Yael Y Lebenthal Yael Y Gharavi Ali G AG Krzemień Grażyna G GG Miklaszewska Monika M Steiner Robert D RD Raggio Cathy C Blank Robert R Baris Feldman Hagit H Milo Rasouly Hila H Sobreira Nara L M NLM Jobling Rebekah R Gordon Christopher T CT Giampietro Philip F PF Dunwoodie Sally L SL Chapman Gavin G

Human molecular genetics 20201201 22

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. W ...[more]

PMID: 33276377

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Project description:Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.

Dataset Information

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

Publications

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

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