SLC20A2 – Idiopathic Basal Ganglia Calcification

Idiopathic basal ganglia calcification (IBGC; also known as primary familial brain calcification) is a rare, autosomal dominant disorder characterized by bilateral, symmetric calcifications primarily in the basal ganglia, thalami, and cerebellum. Heterozygous variants in SLC20A2 (HGNC:10947), encoding the type III sodium-dependent phosphate transporter PiT-2, are the predominant genetic cause, accounting for approximately 40% of familial cases. Loss-of-function mutations lead to impaired phosphate homeostasis and ectopic calcium deposition in cerebral microvessels (PMID:23334463).

1. Clinical Validity

Definitive. Multiple independent studies have identified SLC20A2 variants in over 218 IBGC subjects, with segregation in 13 unrelated families and concordant functional data demonstrating PiT-2 loss of function.

2. Genetic Evidence

Autosomal dominant inheritance is established by co-segregation of heterozygous SLC20A2 variants with IBGC in families (PMID:23437308). In one large screen of 218 subjects, 12 distinct pathogenic variants were detected in 13 families, with 31 affected relatives harboring segregating variants (PMID:23334463). The mutation spectrum includes nonsense, frameshift, splice-site, and CNV abnormalities in SLC20A2, consistent with haploinsufficiency.

Representative variant: c.1158C>G (p.Tyr386Ter) (PMID:24969325).

3. Functional Evidence

Moderate. Patient‐derived cells and animal models recapitulate the pathogenic mechanism. Pi transport assays in fibroblasts and iPSC‐derived endothelial cells show significantly reduced phosphate uptake in cells carrying SLC20A2 mutations (PMID:30704756). Slc20a2 knockout mice exhibit elevated CSF inorganic phosphate levels and progressive brain calcifications that mirror human IBGC (PMID:26660102).

4. Conflicting Evidence

A minority of clinically characterized IBGC families lack SLC20A2 mutations, underscoring genetic heterogeneity and the involvement of additional causative genes (e.g., PDGFB, PDGFRB, XPR1, MYORG).

5. Integration & Conclusion

Overall, heterozygous loss-of-function variants in SLC20A2 cause dominant IBGC via PiT-2 haploinsufficiency and disrupted phosphate handling in the neurovascular unit. Robust genetic and functional data support definitive clinical validity. SLC20A2 testing is warranted in patients with unexplained basal ganglia calcifications to inform diagnosis, family counseling, and potential development of targeted therapies, such as splice-modulating antisense oligonucleotides.

Key Take-home: SLC20A2 haploinsufficiency is a definitive cause of autosomal dominant idiopathic basal ganglia calcification, and genetic screening should be integrated into diagnostic work-ups.

References

• PLoS One • 2013 • Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification PMID:23437308
• Neurogenetics • 2014 • First report of a de novo mutation at SLC20A2 in a patient with brain calcification PMID:24969325
• Acta Neurologica Belgica • 2016 • Slc20a2 is critical for maintaining a physiologic inorganic phosphate level in cerebrospinal fluid PMID:26660102
• Biochemical and Biophysical Research Communications • 2019 • SLC20A2 variants cause dysfunctional phosphate transport activity in endothelial cells induced from Idiopathic Basal Ganglia Calcification patients-derived iPSCs PMID:30704756
• Human Mutation • 2015 • Update and Mutational Analysis of SLC20A2: A Major Cause of Primary Familial Brain Calcification PMID:25726928

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