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

First Author  Williamson KA Year  2014
Journal  Am J Hum Genet Volume  94
Issue  2 Pages  295-302
PubMed ID  24462371 Mgi Jnum  J:227879
Mgi Id  MGI:5703708 Doi  10.1016/j.ajhg.2014.01.001
Citation  Williamson KA, et al. (2014) Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects. Am J Hum Genet 94(2):295-302
abstractText  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.
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