title: Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss.
abstract: 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.
authors.affiliation: University Hospital Jena, Institute of Human Genetics, Jena, Germany.
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.forename: Marta
authors.initials: M
authors.lastname: Gandia
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.forename: Anika
authors.initials: A
authors.lastname: Maak
authors.forename: Eva M
authors.initials: EM
authors.lastname: Wicklein
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Florian
authors.initials: F
authors.lastname: Wagner
authors.forename: Antonio
authors.initials: A
authors.lastname: Viñuela
authors.forename: Luis A
authors.initials: LA
authors.lastname: Aguirre
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Hannes
authors.initials: H
authors.lastname: Maier
authors.forename: Isabella
authors.initials: I
authors.lastname: Rau
authors.forename: Sebastian
authors.initials: S
authors.lastname: Giesselmann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D003051:Cochlea; D018389:Codon, Nonsense; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006198:Hair Cells, Auditory / Q000378:metabolism; D006239:Haplotypes; D006367:HeLa Cells; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D018389:Codon, Nonsense; D009124:Muscle Proteins; C433890:SMPX protein, human; C499035:Smpx protein, mouse