Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer

Autor: Robert-Jan Pauw, Anne-Martine R. de Heer, Arjan P.M. de Brouwer, Hannie Kremer, Cor W. R. J. Cremers, Jaap Oostrik, Ronald J.C. Admiraal, Rob W.J. Collin, Tim M. Strom, R.F. Plantinga, Patrick L. M. Huygen
Rok vydání: 2008
Předmět:
Silent mutation
Adult
Male
Genetics and epigenetic pathways of disease [NCMLS 6]
Adolescent
Hearing loss
DNA Mutational Analysis
Biology
GPI-Linked Proteins
TECTA Gene
Genomic disorders and inherited multi-system disorders [IGMD 3]
Exon
Young Adult
Cognitive neurosciences [UMCN 3.2]
Gene Frequency
Perception and Action [DCN 1]
Genetics
medicine
Neurosensory disorders [UMCN 3.3]
Missense mutation
Humans
Point Mutation
splice
Family
Genetic Predisposition to Disease
TECTA
Child
Hearing Loss
Genetics (clinical)
Extracellular Matrix Proteins
Membrane Glycoproteins
Mid-frequency hearing loss
Infant
Exons
Pedigree
Enhancer Elements
Genetic
Genetic defects of metabolism [UMCN 5.1]
Child
Preschool
Female
RNA Splice Sites
medicine.symptom
Functional Neurogenomics [DCN 2]
Immunity
infection and tissue repair [NCMLS 1]
Zdroj: European Journal of Human Genetics, 16, 1430-6
European Journal of Human Genetics, 16, 12, pp. 1430-6
ISSN: 1018-4813
DOI: 10.1038/ejhg.2008.110
Popis: Contains fulltext : 69348.pdf (Publisher’s version ) (Closed access) Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.
Databáze: OpenAIRE
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