Update and Mutational Analysis ofSLC20A2: A Major Cause of Primary Familial Brain Calcification

Abstract

Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Loss-of-function mutations in SLC20A2 gene encoding the type III sodium-dependent phosphate transporter 2 (PiT-2) are also associated with Fahr's disease 67,68 , and likely involve changes in phosphate transport at the BBB that promote regional brain accumulation of inorganic phosphate that subsequently cause calcium phosphate deposition 67 .…”

A new SLC20A2 mutation identified in southern Italy family with primary familial brain calcification

“…Recently, a new review (Lemos et al, 2015) reported a distribution of variants across the SLC20A2 gene: 55 variants present in 55 unrelated patient have been identified in families of diverse ethnicities and only few are recurrent.…”

Brain calcifications and PCDH12 variants

“…The frequencies of theses variants in the patients' respective populations as estimated in ExAC are not inconsistent with a causative effect, as they are in the same frequency ranges as other disease-causing variants in SLC20A2 . 8 Because neither segregation nor functional data are available, it is not possible to conclude about their pathogenicity at this stage.…”

“…2,3 Heterozygous variants causing autosomal dominant PFBC in up to 50% of the families were identified in 4 genes: SLC20A2 , PDGFRB , PDGFB , and XPR1 . 4–8 We previously searched for genes with a cerebral expression pattern similar to the PFBC major causative gene SLC20A2 using the Allen Brain Atlas (brain-map.org/), 9,10 observing a higher SLC20A2 expression in regions affected by calcifications in PFBC. PCDH12 was singled out with the highest significant correlation, 10 and a follow-up analysis with additional brains still shows PCDH12 as the most similar pattern to SLC20A2 , even when compared with the other known PFBC causative genes (table e-1 at Neurology.org/ng).…”