First Report of a De Novo Mutation at SLC20A2 in a Patient with Brain Calcification

Abstract

Primary familial brain calcification (PFBC) is identified by mineralization of the basal ganglia and other brain regions in the absence of known causes. The condition is often inherited in an autosomal dominant pattern and can manifest itself clinically with neuropsychiatric symptoms such as Parkinsonism, headaches, psychosis, and mood swings. Mutations in the SLC20A2 gene account for ~40% of inherited cases, and this gene encodes an inorganic phosphate transporter (PiT-2), a transmembrane protein associated with Pi homeostasis. The p.Y386X mutation in SLC20A2 was identified in a patient who presented migraines, brain calcification, and mild but chronic hypovitaminosis D. SLC20A2 c.1158C > G single-nucleotide heterozygous mutation results in a premature stop codon and a putative truncated protein of 385 amino acids. Proband parents do not present the mutation, which is also not present in major public SNP databases, suggesting a de novo sporadic trait. This study describes for the first time a de novo SLC20A2 mutation in a PFBC patient with migraine and mild hypovitaminosis D. This data further reinforces the pathogenic role of SLC20A2 mutations as causal factors in PFBC physiopathology.

New Studies on Knockout Mouse for the SLC20A2 Gene Show Much More Than Brain Calcifications

“…The SLC20A2 KO was evaluated as a model for human primary familial brain calcification (PFBC) and appears to correlate well with the loss of function mutants found in PFBC patients, where SLC20A2 represents~40-50 % of inherited cases (Ferreira et al 2014). The reported similarities between SLC20A2 KO mouse and human pathologies was striking.…”

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

“…[] reported a nonsense variant (p.Arg172 Fs X19) in exon 8 that showed a ∼30% reduction of SLC20A2 mRNA expression in blood cells, by RT‐PCR, while Ferreira et al. reported a de novo nonsense variant (p.Tyr386*), also in exon 8, with a small decrease in SLC20A2 expression (∼10% less) relative to controls [Ferreira et al., ]. This small difference might be due to compensation by the wild‐type allele triggered by allelic loss or to a stable expression of mutant SLC20A2 .…”

“…Five novel variations recently identified by collaborators are also reported; it includes a total of 50 pathogenic variants (six of which are recurrent, one of them intronic): 22 missense, 13 frameshift, 2 deletions, 7 nonsense, and 6 splice site; comprising a de novo mutation and a large (563,256 bp) genomic deletion affecting multiple genes besides SLC20A2 [Wang et al, 2012;Schottlaender et al, 2012;Hsu et al, 2013;Lemos et al, 2013;Nicolas et al, 2013aNicolas et al, , 2013bZhang et al, 2013;Chen et al, 2013;Kasuga et al, 2014, Loughran et al, 2013Baker et al, 2014;Zhu et al, 2014., Yamada et al, 2014Ferreira et al, 2014;Carecchio et al, 2014;Rubino et al, 2014;Brighina et al, 2014;Taglia et al, 2014]. These variants are extremely rare or absent in major databases, such as the Exome Sequencing Project, 1000 Genomes, dbSNP, or HapMap.…”

“…The abnormal deposits of calcium in the brain occur within families in primary familial brain calcification (PFBC), a heterogeneous neuropsychiatric condition with symptoms that can include migraine, parkinsonism, psychosis, dementia, and mood swings. The term “primary” implies the absence of metabolic, infectious, toxic, or traumatic cause in both sporadic or familial cases, where it is often consistent with autosomal dominant inheritance; however, sporadic presentations might be due either to de novo mutations or to a mutation transmitted by an undiagnosed, asymptomatic parent [Zhang et al., ; Ferreira et al., ]. A variable age of onset is typically reported between 30 and 60 years, with gradual progression [Oliveira, ].…”

Primary familial brain calcification: update on molecular genetics

“…Although the involvement of PiT-1 in bone differentiation and cell mineralization has been deeply investigated, the molecular mechanism of calcification caused by PiT-2 transport dysfunctions is still to be elucidated and further studies are needed. So far, over 40 pathogenic variants in SLC20A2 gene have been reported in patients with PFBC, including missense, frameshift and non-sense mutations, but also deletions and one splice-site mutation; among them, one de novo variant has been found (Table 1) [21]. Missense mutations in PiT-2 protein could impair transport function; for instance, His502 and Glu575, substituted by a glutamine and a lysine, respectively, are critical for Pi transport [2,14,22].…”