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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.

SUBMITTER: Zazo Seco C 

PROVIDER: S-EPMC4667106 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Zazo Seco Celia C   Serrão de Castro Luciana L   van Nierop Josephine W JW   Morín Matías M   Jhangiani Shalini S   Verver Eva J J EJ   Schraders Margit M   Maiwald Nadine N   Wesdorp Mieke M   Venselaar Hanka H   Spruijt Liesbeth L   Oostrik Jaap J   Schoots Jeroen J   van Reeuwijk Jeroen J   Lelieveld Stefan H SH   Huygen Patrick L M PL   Insenser María M   Admiraal Ronald J C RJ   Pennings Ronald J E RJ   Hoefsloot Lies H LH   Arias-Vásquez Alejandro A   de Ligt Joep J   Yntema Helger G HG   Jansen Joop H JH   Muzny Donna M DM   Huls Gerwin G   van Rossum Michelle M MM   Lupski James R JR   Moreno-Pelayo Miguel Angel MA   Kunst Henricus P M HP   Kremer Hannie H  

American journal of human genetics 20151029 5


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.H  ...[more]

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