Mutations in GRHL2 Result in an Autosomal-Recessive Ectodermal Dysplasia Syndrome

Gabriela Petrof,Arti Nanda,Jake Howden,Takuya Takeichi,James R Mcmillan,Sophia Aristodemou,Linda Ozoemena,Lu Liu,Andrew P South,Celine Pourreyron,Dimitra Dafou,Laura E Proudfoot,Hejab Al-Ajmi,Masashi Akiyama,W.H Irwin Mclean,Michael A Simpson,Maddy Parsons,John A Mcgrath

doi:10.1016/j.ajhg.2014.08.001

Abstract

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.

Highlights

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development
GRHL2 (MIM 608576) has been shown to regulate TERT (MIM 187270) expression and to enhance proliferation of epidermal keratinocytes; it impairs keratinocyte differentiation through transcription inhibition of genes clustered at the epidermal differentiation complex[12] and regulates epithelial morphogenesis by establishing functional tight junctions.[13]
GRHL2 is present in the cochlear duct,[14] and mutations in human GRHL2 have been found in progressive autosomal-dominant hearing loss (DFNA28 [MIM 608641]),[15,16] and other polymorphic sequence variants in GRHL2 have been implicated in age-related hearing impairment and noise-induced hearing loss.[17,18,19]

Summary

Introduction

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. We verified potential changes by performing quantitative PCR (qPCR) with RNA from whole skin of three individuals from the two pedigrees, as well as immortalized keratinocytes and primary fibroblasts from one affected person (see Supplemental Data for methods and controls).

Results

Conclusion