Research Article: Confirmation of GRHL2 as the gene for the DFNA28 locus

Date Published: August 27, 2013

Publisher: Wiley Periodicals, Inc.

Author(s): Barbara Vona, Indrajit Nanda, Cordula Neuner, Tobias Müller, Thomas Haaf.

http://doi.org/10.1002/ajmg.a.36017

Abstract

More than 10 years ago, a c.1609_1610insC mutation in the grainyhead-like 2 (GRHL2) gene was identified in a large family with nonsyndromic sensorineural hearing loss, so far presenting the only evidence for GRHL2 being an autosomal-dominant deafness gene (DFNA28). Here, we report on a second large family, in which post-lingual hearing loss with a highly variable age of onset and progression segregated with a heterozygous non-classical splice site mutation in GRHL2. The c.1258-1G>A mutation disrupts the acceptor recognition sequence of intron 9, creating a new AG splice site, which is shifted by only one nucleotide in the 3′ direction. cDNA analysis confirmed a p.Gly420Glufs*111 frameshift mutation in exon 10. © 2013 Wiley Periodicals, Inc.

Partial Text

Autosomal dominant nonsyndromic hearing impairment accounts for approximately 20% of hereditary hearing loss. To date, there are 54 autosomal dominant loci with 27 associated causative genes identified [Van Camp and Smith, 2012]. The DFNA28 (OMIM: 608641) locus is comprised of GRHL2 (OMIM: 608576) with the alias TFCP2L3 (transcription factor cellular promoter 2-like 3), which is a widely expressed transcription factor in human epithelial tissues [Werth et al., 2010]. GRHL2 spans approximately 177 kb on chromosome 8q22.3 (NCBI 37/hg19) and contains 16 exons, which translate into a 625 amino acid protein. It was first associated with the DFNA28 locus through mapping studies involving a five-generation North American family affected with mild to moderate post-lingual progressive bilateral sensorineural hearing loss. In this family, affected members had a heterozygous c.1609_1610insC mutation in exon 13 [Peters et al., 2002]. In addition, several single nucleotide polymorphisms (SNPs) in GRHL2 have been associated with marginal significance with age-related hearing impairment susceptibility [Van Laer et al., 2008]. Considering that a second disease-causing mutation has not been reported, one might begin to suspect that GRHL2 is not a bonafide deafness gene.

The study was approved by the Ethics Committee of the University of Würzburg.

We report on a second DFNA28-causing mutation and the first splice site mutation in GRHL2 in a family affected with non-syndromic hearing loss. Previously, only one mutation in GRHL2 has been associated with hearing loss [Peters et al., 2002]. The mutation described here confirms that mutations in GRHL2 cause postlingual progressive hearing loss. In this light, it may also be worth following up the marginally significant association of presbycusis with GRHL2 variants [Van Laer et al., 2008], using larger cohorts.

 

Source:

http://doi.org/10.1002/ajmg.a.36017

 

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