title: Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function.
abstract: Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1B mutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B-associated alleles because the resulting protein retains some degree of normal function.
authors.affiliation: Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Sabiha
authors.initials: S
authors.lastname: Nazli
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Fareeha
authors.initials: F
authors.lastname: Zulfiqar
authors.forename: Rehan S
authors.initials: RS
authors.lastname: Shaikh
authors.forename: Ahmed U
authors.initials: AU
authors.lastname: Zafar
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Farooq
authors.initials: F
authors.lastname: Sabar
authors.forename: Fouzia T
authors.initials: FT
authors.lastname: Javid
authors.forename: Edward R
authors.initials: ER
authors.lastname: Wilcox
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsilou
authors.forename: Erich T
authors.initials: ET
authors.lastname: Boger
authors.forename: James R
authors.initials: JR
authors.lastname: Sellers
authors.forename: Inna A
authors.initials: IA
authors.lastname: Belyantseva
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001482:Base Composition; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003241:Consanguinity; D018076:DNA, Complementary / Q000235:genetics; D003638:Deafness / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004398:Dyneins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D052245:Usher Syndromes / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018076:DNA, Complementary; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D009218:Myosins; D004398:Dyneins