Heterozygous Loss-of-Function Mutations in YAP1 Cause Both Isolated and Syndromic Optic Fissure Closure Defects

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.

Yap and Taz play a crucial role in neural crest-derived craniofacial development

“…In the absence of the repressive activity from Hippo signaling, Yap and Taz localize to the nucleus and partner with transcription factors, such as transcriptional enhancer activator (TEA) domain (TEAD) family members, to promote gene programs favoring proliferation. Recently, familial studies have shown that heterozygous nonsense mutations in YAP1 are associated with variable phenotypes in the affected families, including orofacial clefting and intellectual disability (Williamson et al, 2014). However, the mechanisms underlying these phenotypic alterations remain unclear.…”

Yap and Taz regulate retinal pigment epithelial cell fate

“…Notable differences occur when yap −/− phenotypes are compared with yap nl13/nl13 phenotypes. The loss of RPE is less evident in yap nl13/nl13 mutants but there is a striking coloboma, similar to that observed in human patients with YAP1 mutations (Williamson et al, 2014). We have not resolved why coloboma is evident in this mutant, but one intriguing possibility is that it could be a consequence of compromised RPE generation in the ventral retina.…”

“…WNT, BMP and TGFβ signaling all control aspects of RPE/NR development through the control of Smads and β-catenin (Sinn and Wittbrodt, 2013;Fuhrmann et al, 2014), both of which have been shown to interact with Yap or Taz (Varelas et al, 2010;Azzolin et al, 2012 (Fossdal et al, 2004;Williamson et al, 2014). SCRA patients carry an autosomal dominant mutation in the Yap-binding domain of TEAD1 and the loss of central RPE in these patients mimics the phenotypes observed in zebrafish yap −/− and Tead1a Y417H overexpression embryos (Fossdal et al, 2004;Jonasson et al, 2007).…”

“…The nl13 mutation was localized between Zv2560 and Zv8353 on chromosome 18 using bulked segregant analysis with SSLPs. yap lies within this interval and, given that mutations in human YAP1 can lead to isolated and syndromic coloboma (Williamson et al, 2014), this gene was a good candidate for harboring the mutation. The genomic mutation was identified as a single base change from A to T in the splice acceptor site of intron 4.…”

“…Furthermore, heterozygous loss-of-function mutations in YAP1 in humans can result in autosomal dominant coloboma and a mutation within the Yap-binding domain of TEAD1 causes Sveinsson's chorioretinal atrophy (SCRA), an autosomal dominant loss of RPE, choroid, and photoreceptors radiating from the optic nerve head (Fossdal et al, 2004;Williamson et al, 2014). Although these mutations and associated diseases have been described, the mechanism(s) underlying the defects is unknown.…”