WFS1 and non-syndromic low-frequency sensorineural hearing loss: a novel mutation in a Portuguese case.
Low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of HL in which frequencies at 2,000 Hz and below are predominantly affected. Most of the families with LFSNHL carry missense mutations in WFS1 gene, coding for wolframin. A Portuguese patient aged 49, reporting HL since her third decade of life, and also referring tinnitus, was shown to display bilateral moderate LFSNHL after audiological evaluation. Molecular analysis led to the identification of a novel mutation, c.511G>A (p.Asp171Asn), found in heterozygosity in the exon 5 of the WFS1 gene, and changing the aspartic acid at position 171 to an asparagine, in the extracellular N-terminus domain of the wolframin protein. This novel mutation wasn't present either in 200 control chromosomes analyzed or in the hearing proband's half-brother, and it had not been reported in 1000 Genomes, Exome Variant Server, HGMD or dbSNP databases. No mutations were found in GJB2 and GJB6 genes. Multi-alignment of 27 wolframin sequences from mammalian species, against the human wolframin sequence in ConSurf, indicated a conservation score corresponding to 7 in a 1-9 color scale where 9 is conserved and 1 is variable. In addition, the mutation p.Asp171Asn was predicted to be damaging and possibly damaging by SIFT and Polyphen-2, respectively. The auditory phenotype of this patient could thus be due to the novel mutation p.Asp171Asn. Further functional characterization might enable to elucidate in which way the change in the residue 171, as other changes introduced by LFSNHL-associated mutations previously described, leads to this type of HL.
Centre for Biodiversity, Functional, and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisbon, Portugal. Electronic address: claudiagoncalves030@gmail.com.
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Gonçalves
Centre for Biodiversity, Functional, and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisbon, Portugal.
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Matos
Centre for Biodiversity, Functional, and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisbon, Portugal.
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Simões-Teixeira
Hospital Santa Maria (Centro Hospitalar de Lisboa Norte, E.P.E.), Lisbon, Portugal.
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Pimenta Machado
Hospital Santa Maria (Centro Hospitalar de Lisboa Norte, E.P.E.), Lisbon, Portugal.
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Simão
Hospital Santa Maria (Centro Hospitalar de Lisboa Norte, E.P.E.), Lisbon, Portugal.
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Dias
Hospital Santa Maria (Centro Hospitalar de Lisboa Norte, E.P.E.), Lisbon, Portugal.
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Andrea
Centre for Biodiversity, Functional, and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisbon, Portugal.
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Fialho
Centre for Biodiversity, Functional, and Integrative Genomics (BioFIG), Faculty of Sciences, University of Lisbon, Portugal; School of Health, Polytechnic Institute of Setúbal, Portugal.
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Caria
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001301:Audiometry, Pure-Tone; D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins; D004247:DNA / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011174:Portugal
D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C114987:wolframin protein; D000072259:Connexin 26; D004247:DNA
LFSNHL; Novel mutation; Wolframin