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


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

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The American Journal of Human Genetics





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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.


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


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



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