Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42

Authors

• Guntram Borck, University of CologneFollow
• Atteeq Ur Rehman, National Institute on Deafness and Other Communication Disorders, National Institutes of Health
• Kwanghyuk Lee, Baylor College of Medicine
• Hans-Martin Pogoda, University of Cologne
• Naseebullah Kakar, BUITEMS
• Simon von Ameln, University of Cologne
• Nicolas Grillet, The Scripps Research Institute
• Michael S. Hildebrand, University of Iowa
• Zubair M. Ahmed, University of Cincinnati
• Gudrun Nürnberg, University of Cologne
• Muhammad Ansar, Quaid-i-Azam University
• Sulman Basit, Quaid-i-Azam University
• Qamar Javed, Quaid-i-Azam University
• Robert J. Morell, National Institute on Deafness and Other Communication Disorders, National Institutes of Health
• Nabilah Nasreen, BUITEMS
• A. Eliot Shearer, University of Iowa
• Adeel Ahmad, Mayo Hospital
• Kimia Kahrizi, University of Social Welfare and Rehabilitation Sciences
• Rehan S. Shaikh, University of the Punjab
• Rana A. Ali, University of the Punjab
• Shaheen N. Khan, University of the Punjab
• Ingrid Goebel, University of Cologne
• Nicole C. Meyer, University of Iowa
• William J. Kimberling, Boys Town National Research Hospital
• Jennifer A. Webster, Translational Genomics Research Institute
• Dietrich A. Stephan, Institute for Individualized Health (IGNITE)
• Martin Schiller, University of Nevada, Las VegasFollow
• Melanie Bahlo, The Walter and Eliza Hall Institute of Medical Research
• Hossein Najmabadi, University of Social Welfare and Rehabilitation Sciences
• Gillespie G. Gillespie, Oregon Health & Science University
• Peter Nürnberg, University of Cologne
• Bernd Wollnik, University of Cologne
• Saima Riazuddin, University of Cincinnati
• Richard J. H. Smith, University of Iowa
• Wasim Ahmad, Quaid-i-Azam University
• Ulrich Müller, The Scripps Research Institute
• Matthias Hammerschmidt, University of Cologne
• Thomas B. Friedman, National Institute on Deafness and Other Communication Disorders, National Institutes of Health
• Sheikh Riazuddin, University of Health Sciences
• Suzanne M. Leal, Baylor College of Medicine
• Jamil Ahmad, BUITEMS
• Christian Kubisch, University of Cologne

Document Type

Article

Publication Date

2-11-2011

Publication Title

The American Journal of Human Genetics

Volume

88

Issue

2

First page number:

127

Last page number:

137

Abstract

By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.

Keywords

Cell receptors; Chromosome Mapping; Chromosomes; Human; Pair 3/genetics; Codon; Nonsense/genetics; Consanguinity; Deafness; Ear; Inner; Female; Gene mapping; Genealogy; Genes; Genes; Recessive/genetics; Genetic Linkage; Genetic Predisposition to Disease; Genetics; Genotype; Hearing Loss/genetics; Humans; Human chromosomes; Human gene mapping; Human genetics; In situ hybridization; Linkage (Genetics); Lod Score; Male; Men; Mice; Mice—Genetics; Nonsense mutation; Pedigree; Receptors; Cell Surface/genetics; Zebra danio; Zebrafish

Disciplines

Genetics and Genomics | Life Sciences | Medical Sciences | Molecular Biology

Language

English

Repository Citation

Borck, G., Rehman, A. U., Lee, K., Pogoda, H., Kakar, N., von Ameln, S., Grillet, N., Hildebrand, M. S., Ahmed, Z. M., Nürnberg, G., Ansar, M., Basit, S., Javed, Q., Morell, R. J., Nasreen, N., Shearer, A. E., Ahmad, A., Kahrizi, K., Shaikh, R. S., Ali, R. A., Khan, S. N., Goebel, I., Meyer, N. C., Kimberling, W. J., Webster, J. A., Stephan, D. A., Schiller, M., Bahlo, M., Najmabadi, H., Gillespie, G. G., Nürnberg, P., Wollnik, B., Riazuddin, S., Smith, R. J., Ahmad, W., Müller, U., Hammerschmidt, M., Friedman, T. B., Riazuddin, S., Leal, S. M., Ahmad, J., Kubisch, C. (2011). Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42. The American Journal of Human Genetics, 88(2), 127-137.
http://dx.doi.org/10.1016/j.ajhg.2010.12.011