TY - JOUR
T1 - Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42
AU - Borck, Guntram
AU - Rehman, Atteeq Ur
AU - Lee, Kwanghyuk
AU - Pogoda, Hans Martin
AU - Kakar, Naseebullah
AU - Von Ameln, Simon
AU - Grillet, Nicolas
AU - Hildebrand, Michael S.
AU - Ahmed, Zubair M.
AU - Nürnberg, Gudrun
AU - Ansar, Muhammad
AU - Basit, Sulman
AU - Javed, Qamar
AU - Morell, Robert J.
AU - Nasreen, Nabilah
AU - Shearer, A. Eliot
AU - Ahmad, Adeel
AU - Kahrizi, Kimia
AU - Shaikh, Rehan S.
AU - Ali, Rana A.
AU - Khan, Shaheen N.
AU - Goebel, Ingrid
AU - Meyer, Nicole C.
AU - Kimberling, William J.
AU - Webster, Jennifer A.
AU - Stephan, Dietrich A.
AU - Schiller, Martin R.
AU - Bahlo, Melanie
AU - Najmabadi, Hossein
AU - Gillespie, Peter G.
AU - Nürnberg, Peter
AU - Wollnik, Bernd
AU - Riazuddin, Saima
AU - Smith, Richard J.H.
AU - Ahmad, Wasim
AU - Müller, Ulrich
AU - Hammerschmidt, Matthias
AU - Friedman, Thomas B.
AU - Riazuddin, Sheikh
AU - Leal, Suzanne M.
AU - Ahmad, Jamil
AU - Kubisch, Christian
N1 - Funding Information:
We wish to thank the family members for their invaluable participation and cooperation. We thank Dennis Drayna and Changsoo Kang for critically reading the manuscript. This work was funded by the Deutsche Forschungsgemeinschaft (DFG; BO2985/3-1; to G.B.), the European Commission FP6 Integrated Project EUROHEAR, Grant LSHG-CT-20054-512063 (to B.W. and C.K.), NIH RO1 DC002842 (to R.J.H.S), NHMRC Career Development Award (to M.B.), NHMRC Overseas Biomedical Fellowship (to M.S.H.), Doris Duke Fellowship (to A.E.S), NIH DC007704 and Skaggs Institute for Chemical Biology (to U.M.), NIH intramural funds from NIDCD DC000039-14 (to T.B.F.), Higher Education Commission (HEC), Government of Pakistan (to W.A.), NIH-NIDCD grant DC03594 (to S.M.L.), and the ICGEB, Trieste, Italy (to Sheikh R.). J.A. thanks Dost Muhammad Baloch and Ahmed Farooq Bazai, VC, BUITEMS, for faculty funds. Genotyping services were partially provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, Contract Number N01-HG-65403 (to S.M.L.).
PY - 2011/2/11
Y1 - 2011/2/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.12.011
DO - 10.1016/j.ajhg.2010.12.011
M3 - Article
C2 - 21255762
AN - SCOPUS:79851516880
SN - 0002-9297
VL - 88
SP - 127
EP - 137
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -