1. Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2
- Author
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Zazo Seco, Celia, Serrão de Castro, Luciana, van Nierop, Josephine W, Morín, Matías, Jhangiani, Shalini, Verver, Eva J J, Schraders, Margit, Maiwald, Nadine, Wesdorp, Mieke, Venselaar, Hanka, Spruijt, Liesbeth, Oostrik, Jaap, Schoots, Jeroen, van Reeuwijk, Jeroen, Lelieveld, Stefan H, Huygen, Patrick L M, Insenser, María, Admiraal, Ronald J C, Pennings, Ronald J E, Hoefsloot, Lies H, Arias-Vásquez, Alejandro, de Ligt, Joep, Yntema, Helger G, Jansen, Joop H, Muzny, Donna M, Huls, Gerwin, van Rossum, Michelle M, Lupski, James R, Moreno-Pelayo, Miguel Angel, Kunst, Henricus P M, and Kremer, Hannie
- Subjects
Male ,Stem Cell Factor ,Reverse Transcriptase Polymerase Chain Reaction ,Genetic Linkage ,Fluorescent Antibody Technique ,Hearing Loss, Unilateral ,Prognosis ,Real-Time Polymerase Chain Reaction ,Pedigree ,Mice ,Phenotype ,Mutation ,NIH 3T3 Cells ,Animals ,Humans ,Female ,Waardenburg Syndrome ,RNA, Messenger ,Alleles - 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.
- Published
- 2015