Abstract
Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in SLC20A2 [NM_001257180.2; c.806delC, p.(Pro269Glnfs*49) and c.1154delG, p.(Ser385Ilefs*70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in PDGFB were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to SLC20A2 haploinsufficiency among the affected family members. The c.456+1G>C mutation in PDGFB resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in SLC20A2 and PDGFB, which broadened and enriched the PFBC mutation spectrum.
Highlights
Primary familial brain calcification (PFBC, OMIM #213600) is a rare neurodegenerative disorder characterized by vascular calcification affecting multiple brain regions, the basal ganglia, thalamus, subcortical white matter, and cerebellum (Nicolas et al, 2013a, 2015; Tadic et al, 2015; Batla et al, 2017)
We evaluated the impact of the c.806delC mutation on SLC20A2 mRNA expression and found a 40–65% relative level in heterozygous carriers compared with controls, confirming that SLC20A2 haploinsufficiency causes brain calcification in the HB-PFBC family members (Figure 1D)
We evaluated the pathogenicity of the c.1154delG variation in SLC20A2 (NM_001257180.2) in ten functionpredicting scoring systems (ACMG, DDIG-in, FATHMM-Indel, MutPred-LOF, PROVEAN, SIFT-Indel, CADD/CADD-Splice, CAPICE/GAVIN, MutationTaster, and VEST/VEST-Indel), three software programs providing conservation scores (GERP++, phyloP100way, and phastCons100way), and four variation databases, most of which supported the deleterious effect of this variation (Table 2)
Summary
Primary familial brain calcification (PFBC, OMIM #213600) is a rare neurodegenerative disorder characterized by vascular calcification affecting multiple brain regions, the basal ganglia, thalamus, subcortical white matter, and cerebellum (Nicolas et al, 2013a, 2015; Tadic et al, 2015; Batla et al, 2017). A similar splice donor site mutation, c.456+1G>A, was reported in a nuclear family, and predicted to lead to exon 4 (NM_002608.4) skipping and introduction of a frameshift version of PDGFB Both patients in the nuclear family had a severe migraine, a history of depression, and calcification in the basal ganglia, thalamus (only mother affected), cerebral cortex (only proband affected), and subcortical white matter (Ramos et al, 2018). Another splice acceptor site mutation in the same intron (c.457-1G>T) may lead to exon 5 (NM_002608.4) skipping and frameshift protein in carriers, leading to chronic headache and intellectual disability (Sekine et al, 2019). The relationship between impaired PDGFB-PDGFRB signaling and brain calcification requires further examination
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