Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
Genetics and Genomics | Mental and Social Health | Psychiatry | Psychiatry and Psychology
X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.
DOI of Published Version
Eur J Hum Genet. 2016 Apr;24(4):550-5. Epub 2015 Aug 5. Link to article on publisher's site
European journal of human genetics : EJHG
Protasova MS, Grigorenko AP, Tyazhelova TV, Andreeva TV, Reshetov DA, Gusev FE, Laptenko AE, Kuznetsova IL, Goltsov AY, Klyushnikov SA, Illarioshkin SN, Rogaev EI. (2016). Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry. Psychiatry Publications and Presentations. https://doi.org/10.1038/ejhg.2015.139. Retrieved from https://escholarship.umassmed.edu/psych_pp/799