title: SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia.
abstract: Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Strongosky
authors.forename: Monica Y
authors.initials: MY
authors.lastname: Sanchez-Contreras
authors.forename: Shan
authors.initials: S
authors.lastname: Yang
authors.forename: Will
authors.initials: W
authors.lastname: Ferguson
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: Susan
authors.initials: S
authors.lastname: Calne
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allanson
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Broderick
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001479:Basal Ganglia / Q000473:pathology*; D001927:Brain Diseases / Q000235:genetics; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D002170:Canada; D002872:Chromosome Deletion; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics*; D004421:Dystonia / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D016678:Genome; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C493589:SLC20A2 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; C474080:THAP1 protein, human