Nonsense Mutations in SMPX, Encoding a Protein Responsive to Physical Force, Result in X-Chromosomal Hearing Loss Antje K. Huebner, Marta Gandia, Peter.

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Nonsense Mutations in SMPX, Encoding a Protein Responsive to Physical Force, Result in X-Chromosomal Hearing Loss Antje K. Huebner, Marta Gandia, Peter Frommolt, Anika Maak, Eva M. Wicklein, Holger Thiele, Janine Altmüller, Florian Wagner, Antonio Viñuela, Luis A. Aguirre, Felipe Moreno, Hannes Maier, Isabella Rau, Sebastian Gießelmann, Gudrun Nürnberg, Andreas Gal, Peter Nürnberg, Christian A. Hübner, Ignacio del Castillo, Ingo Kurth The American Journal of Human Genetics Volume 88, Issue 5, Pages 621-627 (May 2011) DOI: 10.1016/j.ajhg.2011.04.007 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Phenotype and Segregation Analysis in a German Family Affected by Hereditary Hearing Loss (A) Audiograms of selected family members (red indicates the right ear, and blue indicates the left ear). Hearing loss in males typically starts between ages 3–7, whereas hearing loss in females begins in the second to third decades. (B) Haplotypes constructed by four Xp22.12 SNP markers mapped the disease locus between rs1482816 (hg19 X: 5746140) and rs1557901 (hg 19 X: 23222925). Individuals I-1–I-4, III-4, III-6, IV-1, and V-1 were not subjected to the 10K GeneChip linkage analysis. The American Journal of Human Genetics 2011 88, 621-627DOI: (10.1016/j.ajhg.2011.04.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of Nonsense Mutations in SMPX (A) Sequencing of genomic DNA revealed the SMPX nonsense mutations c.109G>T in exon 3 in the German family (left) and c.175G>T in exon 4 in the Spanish family14 (right). Electropherograms of a respective heterozygous female carrier and a hemizygous male are shown in comparison to a reference sequence. No additional mutations have been identified in a cohort of 34 GJB2-negative individuals with early-onset hearing loss. (B) SMPX is composed of five exons (left, the coding sequence is given in blue) and encodes an 88 amino acid protein (right) without known functional domains. The American Journal of Human Genetics 2011 88, 621-627DOI: (10.1016/j.ajhg.2011.04.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Heterologous Expression of the SMPX Mutant Proteins (A) C-terminally Myc-tagged human SMPX (SMPX_myc) was overexpressed in HeLa cells. Costaining with Myc (Santa Cruz, A14 sc-789) and vinculin antibodies (Chemikon MAB3574) revealed overlap, especially in the focal adhesion sites of the cell periphery. Enlargements of the cell membrane (white rectangles) are given. Note that SMPX_myc was largely absent from the mature focal adhesions that serve as anchor points for actin stress fibers (right, arrowheads). The scale bar indicates 5μm. (B) Truncated SMPX (SMPX_59X_myc) revealed an intracellular staining in HeLa cells; the signal was largely absent from adhesion sites at the cell membrane, indicating partial mislocalization of the protein. Enlargements of the cell membrane (white rectangles) are given on the right. SMPX_37X_myc, corresponding to the mutation identified in the German family, was not detectable with Myc antibodies after heterologous expression in HeLa cells (not shown). The scale bar indicates 5μm. The American Journal of Human Genetics 2011 88, 621-627DOI: (10.1016/j.ajhg.2011.04.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Localization of Smpx in the Mouse Inner Ear (A) A schematic representation of the cochlea. The sensory epithelium is composed of inner hair cells (IHC) and outer hair cells (OHC). Nonsensory supporting cells include Deiters cells (DC), Böttcher cells (BC), and inner and outer pillar cells (iPC, oPC). Root cells (RC) build up a cellular network in the lateral wall of the cochlea. (B) Cryosections (7-μm thickness) from the cochlea of adult C57BL/6J mice were stained with an Smpx antibody (Sigma Aldrich #AV41597, 1:500, green), and DAPI (blue). The overlay with differential interference contrast is shown. The scale bar represents 25μm. Stainings of SMPX_myc overexpressing HeLa cells with the Smpx rabbit-antiserum gave the same signal as with the mouse Myc-antibody (data not shown). (C and D) Enlargements of spiral ligament cells and outer sulcus cells together with root cells (C) and the sensory epithelium with supporting cells (D). Note the Smpx localization in root cells, Böttcher cells, inner and outer pillar cell, and weaker signals in Deiters cells and hair cells (marked by arrows). (E) Apical basilar membranes of fixed cochleae were dissected and immunostained with an Smpx antibody (green) and conjugated phalloidin (red). Weak Smpx immunoreactivity was detected in inner and outer hair cells. The scale bar indicates 5μm. The American Journal of Human Genetics 2011 88, 621-627DOI: (10.1016/j.ajhg.2011.04.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions