Novel pathogenic mutations and copy number variations in the VPS13A Gene in patients with chorea‐acanthocytosis

Abstract

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Speciation with gene flow in equids despite extensive chromosomal plasticity

“…This finding reveals key adaptive changes that participated in the genetic makeup of each equine species, with functions involved in cellular interactions (DSG1, NCAN, TBC1D2) and trafficking (MYO5C, ZW10), metabolism (ACCS, SLC9A4, HMGCR), development (SEMA5A, FAT2), olfaction (BPIFB4), and immunity (ITIH4, SIGLEC1). Interestingly, mountain zebras showed positive selection signatures at VPS13A, a gene associated with locomotory and behavioral disorders (23,24), possibly in relation to their high sociability. The antiporter SLC9A4, involved in pH regulation and countering of adverse environmental conditions, was found to be positively selected in plains zebras, which experience a wide range of environments throughout their geographical range.…”

Pilomotor seizure

“…1 Concerning a pedigree with chorea-acanthocytosis in our previous reports, 1,[3][4][5]8 we would like to correct genetics materials associated with our pedigree already revised by Tomiyasu et al 7 In addition to a heterozygous splice site mutation (8035GϾA, transcript variant A [GenBank NM_033305.2]), which we had reported as 8295GϾA (using a different accession number) in the VPS13A genes of the patients (III-2 and III-3), we identified a novel nonsense mutation (1305GϾA, W435X) in the genes of the unaffected mother (II-4) and patients III-2 and III-3. 7 According to them, the inheritance pattern of the pedigree is actually autosomal recessive (pseudodominant).…”

“…1 In their Correction, 1 Saiki et al mention with regret that "an error in sequencing occurred and the inheritance pattern should have been reported as autosomal recessive," with no reference to the recent publication of the full details of the mutations in this family. 7 This Correction effectively changes the impact of the original article and, even more so, its title message. We feel that it would be appropriate to retract the 2003 paper in order to reduce further confusion in the literature.…”

Pilomotor seizure: When paroxysmal gooseflesh heralds brain tumor

“…Tomiyasu et al 7 noted that the proband reported by Saiki et al is indeed compound heterozygous for mutations in the VPS13A (CHAC ) gene and, therefore, a typical recessive ChAc case. Subsequent to the publication of this report, we found the Correction only via PubMed but missed the original Correction in Neurology.…”