Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction

Abstract

We identified overlapping homozygous regions within the DFNB84 locus in a nonconsanguineous Dutch family and a consanguineous Moroccan family with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). The critical region of 3.17 Mb harbored the PTPRQ gene and mouse models with homozygous mutations in the orthologous gene display severe hearing loss. We show that the human PTPRQ gene was not completely annotated and that additional, alternatively spliced exons are present at the 5' end of the gene. Different PTPRQ isoforms are encoded with a varying number of fibronectin type 3 (FN3) domains, a transmembrane domain, and a phosphatase domain. Sequence analysis of the PTPRQ gene in members of the families revealed a nonsense mutation in the Dutch family and a missense mutation in the Moroccan family. The missense mutation is located in one of the FN3 domains. The nonsense mutation results in a truncated protein with only a small number of FN3 domains and no transmembrane or phosphatase domain. Hearing loss in the patients with PTPRQ mutations is likely to be congenital and moderate to profound and most severe in the family with the nonsense mutation. Progression of the hearing loss was observed in both families. The hearing loss is accompanied by vestibular dysfunction in all affected individuals. Although we show that PTPRQ is expressed in many tissues, no symptoms other than deafness were observed in the patients.

Genetics of Nonsyndromic Recessively Inherited Moderate to Severe and Progressive Deafness in Humans

“…However in affected individuals of a Moroccan family, a p.R457G mutation in PTPRQ caused a less severe loss in hearing. The loss in hearing was moderate which had deteriorated with age (Schraders et al, 2010b). Otoacoustic emissions were normal at the age of 13 months.…”

“…Intra-or inter-familal phenotypic variability is also observed due to progression of hearing loss (DFNB7,DFNB8,DFNB25,DFNB30,DFNB59,DFNB72/95,DFNB77,DFNB79,DFNB84 and DFNB91) (Charizopoulou et al, 2011;de Heer et al, 2011;Ebermann et al, 2007b;Grillet et al, 2009;Li et al, 2010;Rehman et al, 2011;Schraders et al, 2010a;Schraders et al, 2010b;Sirmaci et al, 2010;Walsh et al, 2002;Weegerink et al, 2011). Younger individuals with mutations in BSND (DFNB73) also have a less severe degree of hearing loss which suggests a progressive nature of their hearing loss .…”

“…Congenital hearing loss which has been shown to be progressive in nature is associated with mutations in PTPRQ, a gene which encodes a phosphatase specific for phoshatidyl inositol, PI(4,5) P2 (Schraders et al, 2010b;Seifert et al, 2003). PI(4,5) P2 plays an important part in actin remodeling.…”

Does PtdIns(4,5)P2 concentrate so it can multi-task?

“…There are numerous examples, all leading to severe and, in many cases, extremely common diseases. Some of the most prominent include elevated PI3K signalling in cancer [2], re-direction of host cell PtdIns(4,5)P 2 metabolism by bacterial [3] or viral [4] pathogens and genetic diseases caused by loss of enzymes that degrade PtdIns(4,5)P 2 [5][6][7]. In each case, subsets of PtdIns(4,5)P 2 -dependent processes are affected, rather than global failures of all PtdIns(4,5)P 2 -dependent PM functions.…”

Gene Expression Profiles of the Cochlea and Vestibular Endorgans

“…LOXHD1 and GIPC3 are not components of the stereocilia; however, mutations in these genes in mice were shown to lead to degeneration of the stereocilia. [43][44][45] All of these genes are only expressed in the IHCs and OHCs.…”