Pure Cerebellar Ataxia with Homozygous Mutations in the lass="a-plus-plus">PNPLA6 Gene

详细信息    查看全文

• 作者：Sarah Wiethoff ; Conceição Bettencourt ; Reema Paudel ; Prochi Madon…
• 关键词：Cerebellar ataxia ; Gene ; Mutations ; PNPLA6
• 刊名：The Cerebellum
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：16
• 期：1
• 页码：262-267
• 全文大小：960KB
• 刊物主题：Neurosciences; Neurology; Neurobiology;
• 出版者：Springer US
• ISSN：1473-4230
• 卷排序：16

文摘

Autosomal-recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous conditions primarily affecting the cerebellum. Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations in a field where the genotype-phenotype correlations are rapidly expanding. We identified two cousins from a consanguineous family belonging to a large Zoroastrian (Parsi) family residing in Mumbai, India, who presented with pure cerebellar ataxia without chorioretinal dystrophy or hypogonadotropic hypogonadism. We used a combined approach of clinical characterisation, homozygosity mapping, whole-exome and Sanger sequencing to identify the genetic defect in this family. The phenotype in the family was pure cerebellar ataxia. Homozygosity mapping revealed one large region of shared homozygosity at chromosome 19p13 between affected individuals. Within this region, whole-exome sequencing of the index case identified two novel homozygous missense variants in the PNPLA6 gene at c.3847G>A (p.V1283M) and c.3929A>T (p.D1310V) in exon 32. Both segregated perfectly with the disease in this large family, with only the two affected cousins being homozygous. We identified for the first time PNPLA6 mutations associated with pure cerebellar ataxia in a large autosomal-recessive Parsi kindred. Previous mutations in this gene have been associated with a more complex phenotype but the results here suggest an extension of the associated disease spectrum.