title: Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry.
abstract: 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.
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Protasova
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.|Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Anastasia P
authors.initials: AP
authors.lastname: Grigorenko
authors.affiliation: Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Tyazhelova
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Andreeva
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Reshetov
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Fedor E
authors.initials: FE
authors.lastname: Gusev
authors.affiliation: Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.|Department of Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Laptenko
authors.affiliation: Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Irina L
authors.initials: IL
authors.lastname: Kuznetsova
authors.affiliation: Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Goltsov
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Klyushnikov
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Illarioshkin
authors.affiliation: Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.|Department of Genomics and Human Genetics, Laboratory of Evolutionary Genomics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.|Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Rogaev
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics; D002648:Child; D000073840:Copper-Transporting ATPases; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020754:Spinocerebellar Ataxias / Q000235:genetics*
chemical_list: C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases