Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification

Hum Mutat. 2019 Apr;40(4):392-403. doi: 10.1002/humu.23703. Epub 2019 Jan 15.

Abstract

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC.

Keywords: PFBC; SLC20A2; XPR1; functional assay; mutation spectrum; primary familial brain calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Biological Transport
  • Biomarkers
  • Brain Diseases / diagnosis
  • Brain Diseases / genetics*
  • Brain Diseases / metabolism
  • Calcinosis / diagnosis
  • Calcinosis / genetics*
  • Calcinosis / metabolism
  • Cell Line, Tumor
  • China
  • Female
  • Genes, sis
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Neurodegenerative Diseases / diagnosis
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neuroimaging
  • Phenotype
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Virus / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type III / genetics
  • Tomography, X-Ray Computed
  • Xenotropic and Polytropic Retrovirus Receptor

Substances

  • Biomarkers
  • Receptors, G-Protein-Coupled
  • Receptors, Virus
  • SLC20A2 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • XPR1 protein, human
  • Xenotropic and Polytropic Retrovirus Receptor
  • PDGFRB protein, human
  • Receptor, Platelet-Derived Growth Factor beta