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Acta Neurol Scand. 2017 Jul;136(1):59-63. doi: 10.1111/ane.12697. Epub 2016 Oct 10.

Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.

Author information

1
Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
2
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
3
Department of Neurology, Tampere University Hospital, Tampere, Finland.
4
Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
5
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
6
Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal.
7
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
8
Department of Geriatrics, University of Turku, Turku, Finland.
9
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
10
Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland.
11
Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
12
Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
13
Department of Neurology and Clinical Neurophysiology, Lapland Central Hospital, Rovaniemi, Finland.

Abstract

OBJECTIVES:

Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients.

MATERIALS AND METHODS:

A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis.

RESULTS:

Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes.

CONCLUSIONS:

Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.

KEYWORDS:

SLC20A2; deletion; primary familial brain calcification; promoter

PMID:
27726124
DOI:
10.1111/ane.12697
[Indexed for MEDLINE]

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