Mutations in KITLG, encoding KIT ligand, cause unilateral hearing loss. C. Zazo Seco1,2,3, L. S. Serrao de Castro4,5, J. W. van Nierop1,3, M. Schraders1,2,3, E. J. Verver1, M. Morín4,5, N. Maiwald6, M. Wesdrop1, H. Venselaar8, L. Spruijt6, J. Oostrik1,2,3, J. Schoots6, L. H. Hoefsloot6, J. H. Jansen2,7, G. Huls2,7, M. M. Van Rossum9, H. P. Kunst1,3, M. A. Moreno-Pelayo4,5, H. Kremer1,2,3,6, Baylor-Hopkins Center for Mendelian Genomics 1) Department of Otorhinolaryngology, Hearing & Genes, Radboud university medical center, Nijmegen, Netherlands; 2) The Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, Netherlands; 3) Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands; 4) Servicio de Genética, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain; 5) Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; 6) Department of Human Genetics, Radboud university medical center, Nijmegen, Netherlands; 7) Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, Netherlands; 8) Centre for Molecular and Biomolecular Informatics, Radboud university medical center, Nijmegen, Netherlands; 9) Department of Dermatology, Radboud university medical center, Nijmegen, Netherlands.

   Familial nonsyndromic unilateral hearing loss (UHL) is uncommon with very few affected families described in literature. To date, no genes or loci are known to be involved in familial nonsyndromic UHL. In our study, we focused on elucidating the genetic cause underlying HL in a large Dutch family (W09-1628) with congenital, nonsyndromic, unilateral or asymmetric, stable, severe-to-profound HL. The UHL in family W09-1628 is inherited in a dominant manner and exhibits reduced penetrance. Our approach was a combined strategy of linkage analysis and whole exome sequencing which revealed a heterozygous deletion that creates a nonsense mutation in KITLG as the putative cause of the UHL. This mutation segregates with the HL in the family and it is not present in 306 Dutch control alleles, the Exome Variant Server, 1000 Genomes and in the Nijmegen exome database (n=2096). In order to further address the involvement of KITLG mutations in UHL, sequence analysis of the coding regions and splice sites of KITLG was performed in 16 UHL index patients, mostly of Dutch origin, and in 25 UHL index patients from Spanish origin. This revealed a heterozygous deletion in a patient of Spanish origin. This mutation segregates with the HL in the family and it is neither present in 188 Spanish control alleles nor in any variation database described above. The mutation affects a highly conserved cysteine residue involved in a Cys-Cys intramolecular bond. In silico protein modeling predicts that this mutation affects the local structure of the protein and the biological activity of KITLG. KITLG encodes KIT ligand which, after binding to the KIT receptor, triggers a downstream cascade that has an effect on the proliferation, migration and cell survival of melanocytes, hematopoietic stem cells and primordial germ cells. There are mutant mice with semi-dominant mutations in Kit and Kitl that exhibit HL. The HL in the Kit mutant Wv/Wv is unilateral and the mutant allele shows reduced penetrance. The HL in the Kitl mutant Sld/Sld is congenital and severe. In both mutants, the level of hearing seems to be dependent on the number of melanocytes that migrate to the stria vascularis and survive. There, melanocytes are essential for generating the endocochlear potential which is the driving force for sensory hair cell depolarization. Besides the UHL, no further abnormalities were seen in these families with heterozygous mutations in KITLG.

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