Novel mutations confirm that COL11A2 is responsible for autosomal recessive non-syndromic hearing loss DFNB53
| Autor: | Xue Zhong Liu, Denise Yan, Oscar Diaz-Horta, Mariem Bensaid, Guney Bademci, Mustafa Tekin, M'hamed Grati, Qi Ma, Duygu Duman, Amjad Farooq, Saber Masmoudi, A. Chakroun, Imen Chakchouk, Joseph Foster, Rahul Mittal, Abdelmonem Ghorbel |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Models Molecular Genotype Otospondylomegaepiphyseal dysplasia Hearing loss Hearing Loss Sensorineural Genetic counseling Molecular Sequence Data Mutation Missense Genes Recessive Biology Collagen Type XI Article Consanguinity Gene Frequency Genetics medicine Humans Missense mutation Exome Genetic Predisposition to Disease Stickler syndrome Amino Acid Sequence Molecular Biology Exome sequencing Family Health Base Sequence Sequence Homology Amino Acid Sequence Analysis DNA General Medicine medicine.disease Phenotype Pedigree Protein Structure Tertiary Female medicine.symptom Non syndromic |
| Zdroj: | Molecular Genetics and Genomics. 290:1327-1334 |
| ISSN: | 1617-4623 1617-4615 |
| Popis: | Hearing loss (HL) is a major public health issue. It is clinically and genetically heterogeneous. The identification of the causal mutation is important for early diagnosis, clinical follow-up, and genetic counseling. HL due to mutations in COL11A2, encoding collagen type XI alpha-2, can be non-syndromic autosomal-dominant or autosomal-recessive, and also syndromic as in Otospondylomegaepiphyseal Dysplasia, Stickler syndrome type III, and Weissenbacher–Zweymuller syndrome. However, thus far only one mutation co-segregating with autosomal recessive non-syndromic hearing loss (ARNSHL) in a single family has been reported. In this study, whole exome sequencing of two consanguineous families with ARNSHL from Tunisia and Turkey revealed two novel causative COL11A2 mutations, c.109G > T (p.Ala37Ser) and c.2662C > A (p.Pro888Thr). The variants identified co-segregated with deafness in both families. All homozygous individuals in those families had early onset profound hearing loss across all frequencies without syndromic findings. The variants are predicted to be damaging the protein function. The p.Pro888Thr mutation affects a -Gly-X–Y- triplet repeat motif. The novel p.Ala37Ser is the first missense mutation located in the NC4 domain of the COL11A2 protein. Structural model suggests that this mutation will likely obliterate, or at least partially compromise, the ability of NC4 domain to interact with its cognate ligands. In conclusion, we confirm that COL11A2 mutations cause ARNSHL and broaden the mutation spectrum that may shed new light on genotype–phenotype correlation for the associated phenotypes and clinical follow-up. |
| Databáze: | OpenAIRE |
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