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ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency.

Balreira A, Boczonadi V, Barca E, Pyle A, Bansagi B, Appleton M, Graham C, Hargreaves IP, Rasic VM, Lochmüller H, Griffin H, Taylor RW, Naini A, Chinnery PF, Hirano M, Quinzii CM, Horvath R - J. Neurol. (2014)

Bottom Line: Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade.Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other.The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.

ABSTRACT
Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

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Detection of heterozygous ANO10 variants in genomic DNA of patient 1 (a). cDNA analysis of patient 1 detected the c.1843G>A, p.Asp615Asn mutation in hemizygous form, confirming compound heterozygosity (b), Compound heterozygous mutations were detected in patient 2 (c), Q-RT-PCR showed significantly decreased ANO10 mRNA levels in patient 2’s fibroblast, compared with controls (d). Values are expressed as mean ± SD of patient and controls (N = 3)
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Fig1: Detection of heterozygous ANO10 variants in genomic DNA of patient 1 (a). cDNA analysis of patient 1 detected the c.1843G>A, p.Asp615Asn mutation in hemizygous form, confirming compound heterozygosity (b), Compound heterozygous mutations were detected in patient 2 (c), Q-RT-PCR showed significantly decreased ANO10 mRNA levels in patient 2’s fibroblast, compared with controls (d). Values are expressed as mean ± SD of patient and controls (N = 3)

Mentions: Genetic analysis of mitochondrial DNA (mtDNA) for deletions, depletion, and point mutations in muscle DNA as well as direct sequencing of POLG,PDSS1, PDSS2, COQ2, COQ9, CABC1/ADCK3 and APTX in blood DNA were normal in all patients [3]. In patient 1, whole exome sequencing was performed in genomic DNA, isolated from lymphocytes (DNeasy®, Qiagen, Valencia, CA), fragmented and enriched by Illumina TruSeq™ 62 Mb exome capture, and sequenced (Illumina HiSeq 2000, 100 bp paired-end reads). The in-house bioinformatics pipeline included alignment to the human reference genome (UCSC hg19), reformatting, and variant detection (Varscan v2.2, Dindel v1.01), as described previously [8]. On-target variant filtering excluded those with minor allele frequency greater >0.01 in several databases. Rare homozygous and compound heterozygous variants were defined, and protein altering and/or putative ‘disease causing’ mutations, along with their functional annotation, were identified using ANNOVAR [8]. Putative pathogenic variants were confirmed by Sanger sequencing, using custom-designed primers (http://frodo.wi.mit.edu) on an ABI 3130XL (Life Technologies, CA, USA), allowing segregation analyses (Fig. 1a). The primers used for genomic DNA (NG_028216.1) and cDNA (NM_018075.3) analysis of ANO10 are listed in the Supplementary Materials (Supplemental Tables 1 and 2).Fig. 1


ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency.

Balreira A, Boczonadi V, Barca E, Pyle A, Bansagi B, Appleton M, Graham C, Hargreaves IP, Rasic VM, Lochmüller H, Griffin H, Taylor RW, Naini A, Chinnery PF, Hirano M, Quinzii CM, Horvath R - J. Neurol. (2014)

Detection of heterozygous ANO10 variants in genomic DNA of patient 1 (a). cDNA analysis of patient 1 detected the c.1843G>A, p.Asp615Asn mutation in hemizygous form, confirming compound heterozygosity (b), Compound heterozygous mutations were detected in patient 2 (c), Q-RT-PCR showed significantly decreased ANO10 mRNA levels in patient 2’s fibroblast, compared with controls (d). Values are expressed as mean ± SD of patient and controls (N = 3)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Detection of heterozygous ANO10 variants in genomic DNA of patient 1 (a). cDNA analysis of patient 1 detected the c.1843G>A, p.Asp615Asn mutation in hemizygous form, confirming compound heterozygosity (b), Compound heterozygous mutations were detected in patient 2 (c), Q-RT-PCR showed significantly decreased ANO10 mRNA levels in patient 2’s fibroblast, compared with controls (d). Values are expressed as mean ± SD of patient and controls (N = 3)
Mentions: Genetic analysis of mitochondrial DNA (mtDNA) for deletions, depletion, and point mutations in muscle DNA as well as direct sequencing of POLG,PDSS1, PDSS2, COQ2, COQ9, CABC1/ADCK3 and APTX in blood DNA were normal in all patients [3]. In patient 1, whole exome sequencing was performed in genomic DNA, isolated from lymphocytes (DNeasy®, Qiagen, Valencia, CA), fragmented and enriched by Illumina TruSeq™ 62 Mb exome capture, and sequenced (Illumina HiSeq 2000, 100 bp paired-end reads). The in-house bioinformatics pipeline included alignment to the human reference genome (UCSC hg19), reformatting, and variant detection (Varscan v2.2, Dindel v1.01), as described previously [8]. On-target variant filtering excluded those with minor allele frequency greater >0.01 in several databases. Rare homozygous and compound heterozygous variants were defined, and protein altering and/or putative ‘disease causing’ mutations, along with their functional annotation, were identified using ANNOVAR [8]. Putative pathogenic variants were confirmed by Sanger sequencing, using custom-designed primers (http://frodo.wi.mit.edu) on an ABI 3130XL (Life Technologies, CA, USA), allowing segregation analyses (Fig. 1a). The primers used for genomic DNA (NG_028216.1) and cDNA (NM_018075.3) analysis of ANO10 are listed in the Supplementary Materials (Supplemental Tables 1 and 2).Fig. 1

Bottom Line: Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade.Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other.The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.

ABSTRACT
Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

Show MeSH
Related in: MedlinePlus