Journal
JOURNAL OF HUMAN GENETICS
Volume 60, Issue 3, Pages 119-126Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jhg.2014.114
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Funding
- National Basic Research Program of China [2014CB541702]
- National Nature Science Foundation of China [81170923, 81470705, 81300833]
- Special Scientific Research Fund for Public Welfare Industry of the Ministry of Health in China [201302001]
- Natural Science Foundation of Hunan Province, China [14JJ7009, 13JJ4023]
- National Institutes of Health [R01DC005575, R01DC012115]
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Autosomal dominant nonsyndromic hearing loss (ADNSHL/DFNA) is a highly genetically heterogeneous disorder. Hitherto only about 30 ADNSHL-causing genes have been identified and many unknown genes remain to be discovered. In this research, genome-wide linkage analysis mapped the disease locus to a 4.3 Mb region on chromosome 19q13 in SY-026, a five-generation nonconsanguineous Chinese family affected by late-onset and progressive ADNSHL. This linkage region showed partial overlap with the previously reported DFNA4. Simultaneously, probands were analyzed using exome capture followed by next-generation sequencing. Encouragingly, a heterozygous missense mutation, c.505G>A (p.G169R) in exon 3 of the CEACAM16 gene (carcinoembryonic antigen-related cell adhesion molecule 16), was identified via this combined strategy. Sanger sequencing verified that the mutation co-segregated with hearing loss in the family and that it was not present in 200 unrelated control subjects with matched ancestry. This is the second report in the literature of a family with ADNSHL caused by CEACAM16 mutation. Immunofluorescence staining and western blots also prove CEACAM16 to be a secreted protein. Furthermore, our studies in transfected HEK293T cells show that the secretion efficacy of the mutant CEACAM16 is much lower than that of the wild type, suggesting a deleterious effect of the sequence variant.
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