title: Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.
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.
authors.affiliation: 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.
authors.forename: Celia
authors.initials: C
authors.lastname: Zazo Seco
authors.affiliation: 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.
authors.forename: Luciana
authors.initials: L
authors.lastname: Serrão de Castro
authors.affiliation: 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.
authors.forename: Josephine W
authors.initials: JW
authors.lastname: van Nierop
authors.affiliation: 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.
authors.forename: Matías
authors.initials: M
authors.lastname: Morín
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Eva J J
authors.initials: EJ
authors.lastname: Verver
authors.affiliation: 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.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Nadine
authors.initials: N
authors.lastname: Maiwald
authors.affiliation: 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.
authors.forename: Mieke
authors.initials: M
authors.lastname: Wesdorp
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.affiliation: 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.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.affiliation: 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.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Lelieveld
authors.affiliation: Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.affiliation: 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.
authors.forename: María
authors.initials: M
authors.lastname: Insenser
authors.affiliation: 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.
authors.forename: Ronald J C
authors.initials: RJ
authors.lastname: Admiraal
authors.affiliation: 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.
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.affiliation: 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vásquez
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: 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.
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: 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.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.affiliation: Department of Dermatology, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: van Rossum
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 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.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.affiliation: 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.
authors.forename: Henricus P M
authors.initials: HP
authors.lastname: Kunst
authors.affiliation: 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.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000483:Alleles; D000818:Animals; D005260:Female; D005455:Fluorescent Antibody Technique; D008040:Genetic Linkage; D046088:Hearing Loss, Unilateral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D012333:RNA, Messenger; D019089:Stem Cell Factor