Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.
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.
Institute of Human Genetics, University of Cologne, Cologne, Germany. guntram.borck@uk-koeln.de
Guntram
G
Borck
Atteeq
A
Ur Rehman
Kwanghyuk
K
Lee
Hans-Martin
HM
Pogoda
Naseebullah
N
Kakar
Simon
S
von Ameln
Nicolas
N
Grillet
Michael S
MS
Hildebrand
Zubair M
ZM
Ahmed
Gudrun
G
Nürnberg
Muhammad
M
Ansar
Sulman
S
Basit
Qamar
Q
Javed
Robert J
RJ
Morell
Nabilah
N
Nasreen
A Eliot
AE
Shearer
Adeel
A
Ahmad
Kimia
K
Kahrizi
Rehan S
RS
Shaikh
Rana A
RA
Ali
Shaheen N
SN
Khan
Ingrid
I
Goebel
Nicole C
NC
Meyer
William J
WJ
Kimberling
Jennifer A
JA
Webster
Dietrich A
DA
Stephan
Martin R
MR
Schiller
Melanie
M
Bahlo
Hossein
H
Najmabadi
Peter G
PG
Gillespie
Peter
P
Nürnberg
Bernd
B
Wollnik
Saima
S
Riazuddin
Richard J H
RJ
Smith
Wasim
W
Ahmad
Ulrich
U
Müller
Matthias
M
Hammerschmidt
Thomas B
TB
Friedman
Sheikh
S
Riazuddin
Suzanne M
SM
Leal
Jamil
J
Ahmad
Christian
C
Kubisch
D000818:Animals; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D003241:Consanguinity; D007758:Ear, Inner; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008126:Lod Score; D008297:Male; D051379:Mice; D010375:Pedigree; D011956:Receptors, Cell Surface / Q000235:genetics*; D015027:Zebrafish
D018389:Codon, Nonsense; C493788:ILDR1 protein, human; D011956:Receptors, Cell Surface
Development. 1996 Dec;123:95-102
9007232
Am J Hum Genet. 2010 Mar 12;86(3):479-84
20170898
J Neurosci. 2007 Feb 28;27(9):2163-75
17329413
Bioinformatics. 2001 Aug;17(8):742-3
11524377
Nat Methods. 2010 Aug;7(8):575-6
20676075
J Biol Chem. 2008 Sep 12;283(37):25650-25659
18644789
Am J Hum Genet. 1998 Jul;63(1):259-66
9634505
Genomics. 2007 Feb;89(2):197-206
17049805
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16899-903
12477932
Cell. 2001 Jan 12;104(1):165-72
11163249
J Hum Genet. 2009 May;54(5):266-70
19287372
Traffic. 2009 Aug;10(8):1098-114
19497050
Bioinformatics. 2005 May 1;21(9):2123-5
15647291
Biochem Biophys Res Commun. 2004 Oct 22;323(3):970-8
15381095
Am J Hum Genet. 2009 Sep;85(3):328-37
19732867
Nat Rev Genet. 2008 Apr;9(4):277-90
18283275
Neuron. 1998 Feb;20(2):271-83
9491988
Clin Genet. 2005 Jan;67(1):61-8
15617550
Am J Med Genet A. 2005 Feb 15;133A(1):18-22
15641023
Annu Rev Genet. 2005;39:9-22
16285850
Neuron. 2010 Oct 21;68(2):293-308
20955936
Am J Hum Genet. 2006 Dec;79(6):1040-51
17186462
Cell. 2009 Oct 2;139(1):33-44
19804752
Am J Hum Genet. 2010 Mar 12;86(3):378-88
20170899
Nat Genet. 2002 Jan;30(1):97-101
11731797
Hum Genet. 2008 Nov;124(4):325-48
18784944
Hum Mol Genet. 1996 Aug;5(8):1187-91
8842739
PLoS Genet. 2008 Jul 25;4(7):e1000137
18654634
Nat Genet. 2000 May;25(1):12-3
10802644
Curr Top Dev Biol. 2008;84:385-429
19186249
Neuroreport. 2000 Nov 27;11(17):R35-44
11117521
Nat Rev Genet. 2004 Jul;5(7):489-98
15211351
Clin Genet. 2006 May;69(5):371-92
16650073
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W20-5
15215342
Am J Hum Genet. 2009 Jul;85(1):25-39
19576567
Diabetes. 2009 May;58(5):1040-9
19188430
Am J Hum Genet. 2003 Nov;73(5):1082-91
13680526