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Am J Hum Genet. 2015 Nov 5;97(5):647-60. doi: 10.1016/j.ajhg.2015.09.011. Epub 2015 Oct 29.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Author information

1
Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
2
Servicio de Genética, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid 28034, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28034, Spain.
3
Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
5
Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
6
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
7
Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
8
The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
9
Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Madrid 28034, Spain.
10
Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
11
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
12
Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Department of Hematology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
13
Department of Dermatology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
14
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
15
Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands. Electronic address: hannie.kremer@radboudumc.nl.

Abstract

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

PMID:
26522471
PMCID:
PMC4667106
DOI:
10.1016/j.ajhg.2015.09.011
[Indexed for MEDLINE]
Free PMC Article

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