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

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.

Analysis of the angulin family consisting of LSR, ILDR1 and ILDR2: tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis

“…Recently, it has been reported that autosomal recessive mutations in the ILDR1 gene cause the familial nonsyndromic deafness DFNB42 (Borck et al, 2011). Given the characteristics of ILDR1 clarified in the present study, it is reasonable to speculate that these mutations impair the roles of ILDR1 in the recruitment of tricellulin to TCs and maintenance of epithelial barrier function.…”

“…To date, ten mutations have been reported to cause DFNB42 (Borck et al, 2011). Among these, one mutation (c.3G.A) alters the initiation codon of hILDR1 and three mutations (c.59-5_88del, c.411delG and c.499+1G.A) cause truncation at the extracellular region of hILDR1.…”

“…On the contrary, R453Q was capable of localizing at TCs and recruiting tricellulin, although it did not seem to undergo NMD. Since the linkage of the R453Q mutation to DFNB42 is relatively low (logarithm of odds score52.1) and the Arg453 residue is not completely conserved among the orthologs and paralogs of ILDR1, Borck et al (Borck et al, 2011) suspended a conclusion about the pathogenicity of the R453Q mutation. Further studies on this mutation will reveal its detailed pathogenicity.…”

“…ILDR1 was originally identified as a protein expressed in lymphoma cells (Hauge et al, 2004). Recently, it has been revealed that ILDR1 is the causative gene for a familial nonsyndromic deafness, DFNB42 (MIM 609646) (Borck et al, 2011). ILDR2 was reported to be a candidate modifier of susceptibility to type 2 diabetes (DokmanovicChouinard et al, 2008).…”

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

“…(17) (R. Chandra and R.A. Liddle, unpublished data). Recently, Ildr1 mRNA has been localized to hair and supporting cells present in the organ of Corti, and it was found that mutations in Ildr1 lead to DFNB42, a type of nonsyndromic autosomal recessive hearing impairment (46). It was recently demonstrated that LSR is essential for the formation of tricellular tight junctions and targeting of tricellulin to these junctions (47).…”