Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42 Guntram Borck, Atteeq Ur Rehman, Kwanghyuk Lee, Hans-Martin Pogoda,

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Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42 Guntram Borck, Atteeq Ur Rehman, Kwanghyuk Lee, Hans-Martin Pogoda, Naseebullah Kakar, Simon von Ameln, Nicolas Grillet, Michael S. Hildebrand, Zubair M. Ahmed, Gudrun Nürnberg, Muhammad Ansar, Sulman Basit, Qamar Javed, Robert J. Morell, Nabilah Nasreen, A. Eliot Shearer, Adeel Ahmad, Kimia Kahrizi, Rehan S. Shaikh, Rana A. Ali, Shaheen N. Khan, Ingrid Goebel, Nicole C. Meyer, William J. Kimberling, Jennifer A. Webster, Dietrich A. Stephan, Martin R. Schiller, Melanie Bahlo, Hossein Najmabadi, Peter G. Gillespie, Peter Nürnberg, Bernd Wollnik, Saima Riazuddin, Richard J.H. Smith, Wasim Ahmad, Ulrich Müller, Matthias Hammerschmidt, Thomas B. Friedman, Sheikh Riazuddin, Suzanne M. Leal, Jamil Ahmad, Christian Kubisch The American Journal of Human Genetics Volume 88, Issue 2, Pages 127-137 (February 2011) DOI: 10.1016/j.ajhg.2010.12.011 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of an ILDR1 Nonsense Mutation Causing Autosomal-Recessive Hearing Impairment (A) Pedigree of family PKDF637 and haplotype analysis showing homozygous haplotypes on chromosome 3q13.3-q21.1 in affected individuals. c.1135G>T (NM_001199799.1) denotes an ILDR1 nonsense mutation leading to p.Glu379X. Mb, megabases from human genome reference sequence build hg19. (B) Sequence chromatograms of a part of ILDR1 exon 7 of an individual homozygous for the reference sequence (wild-type) and an affected individual from family PKDF637 homozygous for the c.1135G>T (p.Glu379X) mutation. (C) Genomic structure of ILDR1 based on the longest open reading frame (NM_001199799.1) containing eight coding exons (black rectangles). The positions of the ten ILDR1 mutations are shown both at the gene (top) and the protein level (bottom). The protein diagram depicts the predicted functional domains and sequence motifs. The nonsense mutation identified in family PKDF637 is highlighted in green and the two identified missense substitutions are shown in red. 14-3-3, 14-3-3 binding site; Arg, arginine-rich region; Cys, cysteine-rich region; diL, dileucine motif; Ig, immunoglobulin superfamily domain; SP, signal peptide; TM, transmembrane domain. (D) Overview of the overlapping linkage intervals on chromosome 3q in family PKDF637 and in the original DFNB42 family (designated DEM4012 in this report). The American Journal of Human Genetics 2011 88, 127-137DOI: (10.1016/j.ajhg.2010.12.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Haplotype Analysis at the DFNB42 Locus and Cosegregation of ILDR1 Mutations with Autosomal-Recessive Hearing Impairment in Ten Families (A) Pedigree of the original DFNB42 family (DEM4012). (B–J) Pedigrees of nine additional families segregating autosomal-recessive hearing impairment. The haplotypes at the DFNB42 locus indicate shared homozygosity in affected individuals in each family. Genotypes of the respective ILDR1 mutations are shown on the haplotypes. Mb, megabases. The American Journal of Human Genetics 2011 88, 127-137DOI: (10.1016/j.ajhg.2010.12.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Representative Audiograms of Hearing-Impaired Individuals Homozygous for ILDR1 Mutations (A) Audiograms of selected individuals from families PKDF637, PKDF899, L-1621, L-867, and DEM4012 showing hearing impairment that is more pronounced at high frequencies. (B) Audiograms of selected individuals from families DEM4089, DEM4098, and DEM4430 showing hearing impairment involving all frequencies similarly. Only audiograms measured from the right ear are shown. Audiograms from the left ear were similar. y, age at time of audiogram in years. The American Journal of Human Genetics 2011 88, 127-137DOI: (10.1016/j.ajhg.2010.12.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of Ildr1 in the Mouse Inner Ear (A) Nonquantitative RT-PCR with exonic Ildr1 primers on cDNA derived from P2 mouse organs. gDNA, genomic DNA; H2O, control PCR with water as a template. (B–E) In situ hybridization of Ildr1 in the mouse cochlea at P4. Antisense (AS) probe (B and D); control sense (S) probe (C and E). Arrowheads in (B) point at the organ of Corti. (F–N) In situ hybridization of Ildr1 in the organ of Corti at high magnification at P1 (F–H), P4 (I–K), and P10 (L–N) with Ildr1 antisense (F, I, L) and sense (G, J, M) probes. Yellow dotted lines in (F), (I), and (L) indicate the positions of inner and outer hair cells. Ildr1 is expressed at low-to-intermediate levels in hair cells and at higher levels in the Pillar and Hensen cells adjacent to hair cells. In (H), (K), and (N), the hair cells are stained with a Loxhd1 antisense probe, which is used as a positive control (i.e., Loxhd1 is highly expressed in hair cells).18 (O) Diagram of Ildr1 expression in the mouse organ of Corti at P4. IHC, inner hair cell; OHC, outer hair cells. Scale bars represent 200 μm in (B) and (C), 100 μm in (D) and (E), and 20 μm in (F)–(N). The American Journal of Human Genetics 2011 88, 127-137DOI: (10.1016/j.ajhg.2010.12.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 5 Expression of ildr1 in Zebrafish Whole-mount in situ hybridization with probes for ildr1 transcripts in wild-type zebrafish embryos and larvae at ages indicated in the bottom left corners. (A, C, D) Lateral views with anterior to the left. (B) Cross section at the level of the posterior lateral line primordium. The inset in (C) depicts a magnification of the ildr1-positive anterior pituitary gland of the 48 hpf larvae. Arrowheads in (D) point to neuromasts, the sensory organs of the lateral line system. ap, anterior pituitary; e, ear; en, endoderm; n, nose; nc, notochord; oc, oral cavity; oe, olfactory epithelium; ov, otic vesicle; pllp, posterior lateral line primordium. The American Journal of Human Genetics 2011 88, 127-137DOI: (10.1016/j.ajhg.2010.12.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions