Title: | Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2 |
Author(s): | Zazo Seco, C.; Castro, L.S. de; Nierop, J.W. van ; Morin, M.; Jhangiani, S.; Verver, E.J.; Schraders, M. ; Maiwald, N.; Wesdorp, F.M.; Venselaar, H. ; Spruijt, L. ; Oostrik, J. ; Schoots, J.; Reeuwijk, J. van ; Lelieveld, S.H.; Huygen, P.L.M. ; Insenser, M.; Admiraal, R.J.C. ; Pennings, R.J.E. ; Hoefsloot, L.H. ; Arias Vasquez, A. ; Ligt, J. de ; Yntema, H.G. ; Jansen, J.H. ; Muzny, D.M.; Huls, G.A.; Rossum, M.M. van ; Lupski, J.R.; Moreno-Pelayo, M.A.; Kunst, H.P.M. ; Kremer, H. |
Publication year: | 2015 |
Source: | American Journal of Human Genetics, vol. 97, iss. 5, (2015), pp. 647-660 |
ISSN: | 0002-9297 |
DOI: | https://doi.org/10.1016/j.ajhg.2015.09.011 |
Publication type: | Article / Letter to editor |
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/152605 ![]() |
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Subject: | Radboudumc 0: Other Research DCMN: Donders Center for Medical Neuroscience Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 12: Sensory disorders RIHS: Radboud Institute for Health Sciences Radboudumc 12: Sensory disorders RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 2: Cancer development and immune defence RIHS: Radboud Institute for Health Sciences Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences |
Organization: | Human Genetics Otorhinolaryngology CMBI Cognitive Neuroscience Psychiatry Laboratory Medicine Haematology Dermatology |
Journal title: |
American Journal of Human Genetics
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Volume: | vol. 97 |
Issue: | iss. 5 |
Page start: | p. 647 |
Page end: | p. 660 |
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.
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