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

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• 作者：Guntram Borck¹ ; ² ; ^{guntram.borck@uk-koeln.de} ; Atteeq Ur Rehman³ ; ⁴ ; ²⁹ ; Kwanghyuk Lee⁵ ; ²⁹ ; Hans-Martin Pogoda⁶ ; ²⁹ ; Naseebullah Kakar⁷ ; ²⁹ ; Simon von Ameln¹ ; ² ; ⁸ ; Nicolas Grillet⁹ ; Michael S. Hildebrand¹⁰ ; Zubair M. Ahmed¹¹ ; Gudrun N&#xfc ; rnberg² ; ¹² ; ¹³ ; Muhammad Ansar¹⁴ ; Sulman Basit¹⁴ ; Qamar Javed¹⁴ ; Robert J. Morell³ ; Nabilah Nasreen⁷ ; A. Eliot Shearer¹⁰ ; Adeel Ahmad¹⁵ ; Kimia Kahrizi¹⁶ ; Rehan S. Shaikh⁴ ; ¹⁷ ; Rana A. Ali⁴ ; Shaheen N. Khan⁴ ; Ingrid Goebel¹ ; ² ; ⁸ ; Nicole C. Meyer¹⁰ ; William J. Kimberling¹⁸ ; Jennifer A. Webster¹⁹ ; Dietrich A. Stephan²⁰ ; ²¹ ; ²² ; Martin R. Schiller²³ ; Melanie Bahlo²⁴ ; Hossein Najmabadi¹⁶ ; Peter G. Gillespie²⁵ ; Peter N&#xfc ; rnberg² ; ¹² ; ¹³ ; Bernd Wollnik¹ ; ² ; ¹³ ; Saima Riazuddin²⁶ ; Richard J.H. Smith¹⁰ ; ²⁷ ; Wasim Ahmad¹⁴ ; Ulrich M&#xfc ; ller⁹ ; Matthias Hammerschmidt² ; ⁶ ; ¹³ ; Thomas B. Friedman³ ; Sheikh Riazuddin²⁸ ; Suzanne M. Leal⁵ ; Jamil Ahmad⁷ ; Christian Kubisch¹ ; ² ; ⁸ ; ¹³
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 February 2011
• 年：2011
• 卷：88
• 期：2
• 页码：127-137
• 全文大小：1125 K

文摘

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.