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

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Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment Margit Schraders, Stefan A. Haas, Nicole J.D. Weegerink, Jaap Oostrik, Hao Hu, Lies H. Hoefsloot, Sriram Kannan, Patrick L.M. Huygen, Ronald J.E. Pennings, Ronald J.C. Admiraal, Vera M. Kalscheuer, Henricus P.M. Kunst, Hannie Kremer The American Journal of Human Genetics Volume 88, Issue 5, Pages 628-634 (May 2011) DOI: 10.1016/j.ajhg.2011.04.012 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Genetic Analyses Only those family members of the large pedigree who were relevant for the study are depicted. The haplotype associated with the hearing impairment is indicated by the gray bar. In individual V.1, allele 3 of marker DXS1043 might be derived from the affected haplotype. The segregation of the c.214G>T is presented above the haplotypes. Family W08-1701 is of Dutch origin and family W05-049 is of Netherlands Antilles' origin. The following symbols are used: black squares, affected males; black circles, affected females; half-shaded circles, females with unilateral hearing impairment; half-shaded square, male with unilateral hearing impairment; gray shaded square, male with hearing impairment less severe than the other affected males. The American Journal of Human Genetics 2011 88, 628-634DOI: (10.1016/j.ajhg.2011.04.012) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Audiometric Characteristics of the Families (A) Representative audiograms (air conduction) of affected men (showing the means of thresholds of the left and right ears) and women (thresholds of left (x) and right ear (o) shown separately) of family W08-1701 demonstrate progressive hearing loss in males within the first two decades and the variability of the hearing loss in females. (B) Representative audiograms of individual IV.1 from family W05-049 at different ages (means of thresholds of the left and right ears are shown). Pure-tone audiometry was performed in a sound-treated room according to current clinical standards. y is an abbreviation for years. The American Journal of Human Genetics 2011 88, 628-634DOI: (10.1016/j.ajhg.2011.04.012) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation and Expression Analysis of SMPX (A and B) Partial SMPX sequence chromatograms are shown for normal controls (upper panels), affected males (middle panels), and female carriers (bottom panels). The predicted amino acid changes and the surrounding amino acids are indicated above the sequence. Mutated nucleotides are marked by an arrowhead. As a reference, we employed sequence NM_014332.1 by using the first ATG translation initiation codon for numbering of the nucleotide change. (C and D) Relative SMPX mRNA expression as determined by quantitative PCR in fetal (C) and adult (D) human tissues. Because this was performed for adult and fetal tissues in two separate experiments, fetal inner ear was included in both for comparison. The American Journal of Human Genetics 2011 88, 628-634DOI: (10.1016/j.ajhg.2011.04.012) Copyright © 2011 The American Society of Human Genetics Terms and Conditions