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.

Prenatal diagnosis of posterior fossa anomalies: Additional value of chromosomal microarray analysis in fetuses with cerebellar hypoplasia

“…There are several chromosome abnormalities that may be associated with CH (Figure ) . Our results further demonstrate that the deletion of 5p15.33, 6q terminal deletion syndrome, and Xq28 duplication syndrome may be related with CH.…”

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

“…More recently, isolated cerebellar hypoplasia without sideroblastic anemia was reported in the affected individuals in one family. These individuals also harbored a deletion on chromosome X, affecting two other genes ( ATP7A and PGAM4 ) that might have influenced the phenotype [ 49 ].…”

The molecular genetics of sideroblastic anemia

“…[42][43][44][45][46][47] In XLSA/A, the anemia tends to be less clinically significant than the cerebellar dysfunction, and, indeed, 1 family with an X-linked ataxia without CSA has been shown to carry a missense allele in ABCB7. 48 The substrate transported by ABCB7 is unclear, but may be an ISC complexed with glutathione. 49 That mutations in ABCB7 result in CSA further suggests that the ontogeny of the ring sideroblast itself in ISC defects might not be consequent to the direct effect on mitochondria, but rather a result of a complex interplay between cytosolic ISC-dependent proteins, such as IRP1, and other mitochondrial pathways, including ALAS2 expression and heme synthesis.…”