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Am J Hum Genet. 2014 Feb 6;94(2):295-302. doi: 10.1016/j.ajhg.2014.01.001. Epub 2014 Jan 23.

Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects.

Author information

1
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
2
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
3
Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK; University College London Institute of Ophthalmology, London EC1V 9EL, UK.
4
Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
5
Département de Génétique, Hôpital Robert-Debré, 75019 Paris, France.
6
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
7
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: david.fitzpatrick@igmm.ed.ac.uk.

Abstract

Exome sequence analysis of affected individuals from two families with autosomal-dominant inheritance of coloboma identified two different cosegregating heterozygous nonsense mutations (c.370C>T [p.Arg124*] and c. 1066G>T [p.Glu356*]) in YAP1. The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting. A combined LOD score of 4.2 was obtained for the association between YAP1 loss-of-function mutations and the phenotype in these families. YAP1 encodes an effector of the HIPPO-pathway-induced growth response, and whole-mount in situ hybridization in mouse embryos has shown that Yap1 is strongly expressed in the eye, brain, and fusing facial processes. RT-PCR showed that an alternative transcription start site (TSS) in intron 1 of YAP1 and Yap1 is widely used in human and mouse development, respectively. Transcripts from the alternative TSS are predicted to initiate at codon Met179 relative to the canonical transcript (RefSeq NM_001130145). In these alternative transcripts, the c.370C>T mutation in family 1305 is within the 5' UTR and cannot result in nonsense-mediated decay (NMD). The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS. Amelioration of the phenotype by the alternative transcripts provides a plausible explanation for the phenotypic differences between the families.

PMID:
24462371
PMCID:
PMC3928658
DOI:
10.1016/j.ajhg.2014.01.001
[Indexed for MEDLINE]
Free PMC Article
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