A DNA Variant within the MYO7A Promoter Regulates YY1 Transcription Factor Binding and Gene Expression Serving as a Potential Dominant DFNA11 Auditory Genetic Modifier

Abstract

Mutations within MYO7A can lead to recessive and dominant forms of inherited hearing loss. We previously identified a large pedigree (referred to as the HL2 family) with hearing loss that first impacts the low and mid frequencies segregating a dominant MYO7A mutation in exon 17 at DNA residue G2164C. The MYO7A G2164C mutation predicts a nonconservative glycine-toarginine (G722R) amino acid substitution at a highly conserved glycine residue. The degree of low and mid frequency hearing loss varies markedly in the family, suggesting the presence of a genetic modifier that either rescues or exacerbates the primary MYO7A G2164C mutation. Here we describe a single nucleotide polymorphism (SNP) T/C at position ؊4128 in the wild-type MYO7A promoter allele that sorts with the degree of hearing loss severity in the pedigree. Electrophoretic mobility shift assay analysis indicates that the SNP differentially regulates the binding of the YY1 transcription factor with the T ؊4128 allele creat- Large human pedigrees segregating monogenic syndromic and nonsyndromic hearing loss have led to the discovery of Ͼ50 genes harboring mutations underlying the sensory deficient within the pedigree (see the Hereditary Hearing Loss homepage on the Internet). Mutations within myosin VIIA (MYO7A) 2 can lead to both syndromic and nonsyndromic hearing impairment in humans. MYO7A is expressed in the retina, testis, lung, kidney, and inner and outer hair cells of the cochlea (2). In hair cells, MYO7A is found in the actin-rich stereocila bundles, cuticular plate, pericuticular necklace, and cell body (3). MYO7A is also expressed in both type I and type II hair cells of the semicircular canals and utricle (3). Syndromic MYO7A mutations are inherited in a recessive fashion, leading to a diagnosis of Usher type 1B (USH1B), a disease characterized by profound, congenital, sensorineural deafness with progressive retinitis pigmentosa leading to visual loss and vestibular areflexia. Nonsyndromic MYO7A mutations can be inherited in either a recessive (DFNB2, the 2nd autosomal recessive deafness locus identified) or dominant (DFNA11, the 11th autosomal dominant deafness locus identified) manner. Five DFNA11 mutations have been characterized: p.delA886-K887-K888 in a Japanese pedigree (4); p.G772R in an American pedigree (5); N458I in a Dutch pedigree (6); p.R853C in a German pedigree (7); and p.A230V in an Italian pedigree (8).We previously mapped the large hearing-impaired DFNA11 American pedigree (referred to as HL2, for hearing loss family 2) to the long arm of chromosome 11 in band 13.5. A MYO7A mutation in exon 17 at DNA residue G2164C was discovered in the HL2 family. The MYO7A G2164C alteration leads to a predicted nonconservative glycine-to-arginine (G772R) amino acid substitution at a highly conserved glycine residue (5). The MYO7A G2164C mutation is unique as it was the first alteration in MYO7A associated with the uncommon clinical finding of progressive low frequency hearing loss (5). We previously showed that the degree of low and mid frequ...

The p.R206C Mutation in <b><i>MYO7A</i></b> Leads to Autosomal Dominant Nonsyndromic Hearing Loss

“…To date, more than 340 different mutations in MYO7A have been documented to be associated with hearing loss (http://www.umd.be/MYO7A/). In contrast, including p.R206C, only 9 mutations have been confirmed to be associated with dominant, nonsyndromic hearing loss DFNA11 [13][14][15][16][17][18][19][20]. Notably, 7 of 9 DFNA11 mutations are located at the motor domain of MYO7A [13][14][15][16][17][18][19][20].…”

Monogenic Causes of Low-Frequency Non-Syndromic Hearing Loss

“…Many MYO7A variants are identified in patients with flat or sloping audiograms. HL severity and frequency range may vary even within the one family [Street et al, 2004] suggesting the existence of a genetic modifier involved in DFNA11 development [Street et al, 2011].…”

Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies

“…The origin of some broadly used cell lines, such as HEK293 or HeLa, is very different from cells implicated in IRDs but they can be equally used to study the function of some genes involved in these blinding disorders [84][85][86][87]. Among others, HEK293 cells have been used by Fuster and collaborators to assess the efficiency of diverse RNA guides designed to target p.Glu767Serfs*21 and p.Cys759Phe mutations in USH2A by CRISPR/Cas9 before using them in patient-derived fibroblasts, widely known to be more difficult to manipulate and transfect [36].…”