The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function.
Pendred syndrome (PS) and DFNB4, a non-syndromic sensorineural hearing loss with enlargement of the vestibular aqueduct (EVA), are caused by mutations in the SLC26A4 gene. Both disorders are recessive, and yet only one mutated SLC26A4 allele, or no mutations, are identified in many cases. Here we present the genetic characterization of 105 Spanish patients from 47 families with PS or non-syndromic EVA and 20 families with recessive non-syndromic hearing loss, which segregated with the DFNB4 locus. In this cohort, two causative SLC26A4 mutations could be characterized in 18 families (27%), whereas a single mutated allele was found in a patient with unilateral hearing loss and EVA in the same ear. In all, 24 different causative mutations were identified, including eight novel mutations. The novel p.Q514K variant was the most prevalent mutation in SLC26A4, accounting for 17% (6/36) of the mutated alleles identified in this study, deriving from a founder effect. We also characterized a novel multiexon 14 kb deletion spanning from intron 3 to intron 6 (g.8091T_22145Cdel). This study also revealed the first case of a de novo recessive mutation p.Q413P causing PS that arose in the proband's paternal allele, the maternal one carrying the p.L445W. The relevance of our results for genetic diagnosis of PS and non-syndromic EVA hearing loss is discussed.
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