In Search of the DFNA11 Myosin VIIA Low- and Mid-Frequency Auditory Genetic Modifier

Kallman, Jeremy C.; Phillips, James O.; Bramhall, Naomi F.; Kelly, John P.; Street, Valerie A.

doi:10.1097/mao.0b013e3181825651

Cited by 7 publications

(5 citation statements)

References 35 publications

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“…1), suggesting the presence of a genetic modifier that either rescues or exacerbates the primary MYO7A G2164C mutation (5). The extent of hearing loss variation in the HL2 pedigree within and between family generations supports the prediction that the putative genetic modifier is a sequence variation commonly found in the general Caucasian population (9). One simple yet elegant mechanism to generate clinical variation within a pedigree segregating a dominant disease would be a single nucleotide polymorphism (SNP) within the wild-type promoter allele that acts in trans either to increase or to decrease expression of the wildtype allele, which is brought into the family by marry-in spouses that are not related genetically to the family members segregating the dominant mutation.…”

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confidence: 52%

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

Street

Robbins

et al. 2011

Journal of Biological Chemistry

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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...

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confidence: 52%

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

Street

Robbins

et al. 2011

Journal of Biological Chemistry

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“…Candidate modifier genes were selected based on their known interaction with MYO7A in hair cells or association with low frequency hearing, and most are members of the Usher type 1 and 2 protein network (Table 4) (23, 24). As it has been suggested that the modifier is a common polymorphism not tightly linked to MYO7A mutations (22), the ATP2B2 ( PMCA2 ) gene, a known deafness modifier (21), was screened for polymorphisms in individual V:3 with a typical DFNB2 presentation, and individual V:2 with atypically mild hearing impairment. Direct sequencing of the entire coding region and splice sites of the ATP2B2 gene did not reveal any polymorphic differences between these individuals, suggesting that the PMCA2 calcium pump does not modify the DFNB2 phenotype in this family (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The existence of a genetic modifier of MYO7A mutations has been suggested based on the variable phenotype of members of an American DFNA11 family (6, 22). Candidate modifier genes were selected based on their known interaction with MYO7A in hair cells or association with low frequency hearing, and most are members of the Usher type 1 and 2 protein network (Table 4) (23, 24).…”

Section: Resultsmentioning

confidence: 99%

“…The existence of a genetic modifier of MYO7A mutation has been proposed based on the variable phenotypic presentation of an American family with progressive hearing impairment and vestibular dysfunction at the DFNA11 locus (6, 22). It has been suggested that this modifier is a common polymorphism not tightly linked to the MYO7A mutation, although the modifier locus has not been identified (22). We considered the possibility of a genetic modifier effect on the phenotypic presentation of affected members of the family L‐1419 based on the better hearing of individual V:2.…”

Section: Discussionmentioning

confidence: 99%

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Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation

et al. 2010

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Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyzes of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. Since one affected family member had significantly less severe hearing loss we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than Usher syndrome type 1B (USH1B), providing further evidence that these two diseases represent discrete disorders.

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“…The mouse offers a powerful system for identifying complex genetic interactions in hearing development and disease because of the availability of numerous strains of mice with different genetic backgrounds (Niu et al 2008). It is clear that genetic factors affect the severity of hearing impairment in humans, but it is much more difficult to identify genetic interaction in humans even when large pedigrees are available (Kallman et al 2008). Due to the conservation of genes among mammals, the identity of candidate modifier genes in humans can be predicted from studies in model organisms such as mice.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment

et al. 2019

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Maternal and fetal sources of thyroid hormone are important for the development of many organ systems. Thyroid hormone deficiency causes variable intellectual disability and hearing impairment in mouse and man, but the basis for this variation is not clear. To explore this variation we studied two thyroid hormone-deficient mouse mutants with mutations in pituitary-specific transcription factors, POU1F1 and PROP1, that render them unable to produce thyroid stimulating hormone. DW/J-Pou1f1dwldw mice have profound deafness and both neurosensory and conductive hearing impairment, while DF/B-Prop1df/df mice have modest elevations in hearing thresholds consistent with developmental delay, eventually achieving normal hearing ability. The thyroid glands of Pou1f1 mutants are more severely affected than those of Prop1df/df mice, and they produce less thyroglobulin during the neonatal period critical for establishing hearing. We previously crossed DW/J-Pou1f1dw/+ and Cast/Ei mice and mapped a major locus on Chromosome 2 that protects against hypothyroidism-induced hearing impairment in Pou1f1dw/dw mice: Modifier of dw hearing (Mdwh). Here we refine that map with additional animals and genotypes, and we conduct novel mapping with a DW/J-Pou1f1dw/+ and 129/P2 cross that reveals 129/P2 mice also have a protective Mdwh locus. Using DNA sequencing of DW/J and DF/B strains, we determined that the genes important for thyroid gland function within Mdwh vary in amino acid sequence between strains that are susceptible or resistant to hypothyroidism-induced hearing impairment. These results suggest that the variable effects of congenital hypothyroidism on the development of hearing ability are attributable to genetic variation in postnatal thyroid gland folliculogenesis and function.

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In Search of the DFNA11 Myosin VIIA Low- and Mid-Frequency Auditory Genetic Modifier

Cited by 7 publications

References 35 publications

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

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

Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation

Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment

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