Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

• Published in: American journal of human genetics Vol. 88; no. 5; pp. 628 - 634
• Main Authors: Schraders, Margit, Haas, Stefan A., Weegerink, Nicole J.D., Oostrik, Jaap, Hu, Hao, Hoefsloot, Lies H., Kannan, Sriram, Huygen, Patrick L.M., Pennings, Ronald J.E., Admiraal, Ronald J.C., Kalscheuer, Vera M., Kunst, Henricus P.M., Kremer, Hannie
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13-05-2011; Cell Press; Elsevier
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; Child, Preschool; Codon, Nonsense; DNA Mutational Analysis; Female; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Gene expression; Gene loci; General aspects. Genetic counseling; Genes, X-Linked; Genetic linkage; Genetics of eukaryotes. Biological and molecular evolution; Hearing loss; Hearing Loss - genetics; Hearing Loss - pathology; Humans; Insulin-Like Growth Factor I - genetics; Male; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Molecular Sequence Annotation; Muscle Proteins - genetics; Muscular system; Mutation; Pedigree; Polymorphism, Single Nucleotide; Proteins; Sequence Analysis; Young Adult; Human; Sex linked character; Nucleotide sequence; Auditory disorder; Protein A; Genetic disease; Progressive; ENT disease; Genetics; Muscle; X-Chromosome; Mutation; Sequencing
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.04.012

In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both.