Unknown

Dataset Information

0

Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

ABSTRACT: Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.

SUBMITTER: Vermeer S 

PROVIDER: S-EPMC2997370 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

Vermeer Sascha S   Hoischen Alexander A   Meijer Rowdy P P RP   Gilissen Christian C   Neveling Kornelia K   Wieskamp Nienke N   de Brouwer Arjan A   Koenig Michel M   Anheim Mathieu M   Assoum Mirna M   Drouot Nathalie N   Todorovic Slobodanka S   Milic-Rasic Vedrana V   Lochmüller Hanns H   Stevanin Giovanni G   Goizet Cyril C   David Albert A   Durr Alexandra A   Brice Alexis A   Kremer Berry B   van de Warrenburg Bart P C BP   Schijvenaars Mascha M V A P MM   Heister Angelien A   Kwint Michael M   Arts Peer P   van der Wijst Jenny J   Veltman Joris J   Kamsteeg Erik-Jan EJ   Scheffer Hans H   Knoers Nine N  

American journal of human genetics 20101118 6

Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation  ...[more]

Similar Datasets

Unknown SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.
| S-EPMC6151335 | biostudies-literature
Unknown Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.
| S-EPMC3567281 | biostudies-literature
Unknown UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.
| S-EPMC4752235 | biostudies-other
Unknown SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
| S-EPMC5540751 | biostudies-literature
Unknown Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34.
| S-EPMC1288574 | biostudies-literature
Unknown Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
| S-EPMC3846781 | biostudies-literature
Unknown Autosomal recessive cerebellar ataxias.
| S-EPMC1664553 | biostudies-literature
Unknown Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.
| S-EPMC4225633 | biostudies-literature
Unknown Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1.
| S-EPMC3511982 | biostudies-literature
Unknown Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.
| S-EPMC6353423 | biostudies-literature