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

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.

%B Am J Hum Genet %V 97 %P 647-60 %8 2015 Nov 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/26522471?dopt=Abstract %R 10.1016/j.ajhg.2015.09.011