Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice

Abstract

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

Occurrence of Fahr's syndrome in patient suffering from systemic lupus erythematosus: A case report

“…Primarna kalcifikacija moždanih struktura obično je autozomno dominantno nasledna (hromozom 14q9) i do sada su otkrivene mutacije na tri gena, SLC2OA2, PDGFB, i PDGFRB. SLC2OA2 je kodiran sa Pit2 fosfatnim transporterom zavisnim od natrijuma, a PDGFB i PDGFRB u vezi su s beta faktorom rasta (27)(28)(29)(30). Skorije studije otkrile su multiple familije sa PFBC mutacijom na XPR1, genom zaduženim za receptor eliminacije fosfora, što utiče na njegovu homeostazu kod PFBC (31).…”

A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

“…1 We only found two mutations: the first one was already reported within the original article, 5 and the second one is the currently presented mutation.…”

“…4 Third, loss of function of PDGF-B (encoded by the PDGFB gene), the main ligand of PDGFRb, has recently been shown to cause IBGC in humans and brain calcification through a disruption of the bloodbrain barrier integrity in mice. 5 Sporadic presentation of IBGC is not uncommon. Nevertheless, true sporadic cases, defined by the absence of basal ganglia calcification in the parents' CT scans after the age of 50, 6 were rarely reported.…”

Lingappa et al. reply

“…6 Information on the platelet-derived growth factor receptor b gene (PDGF-Rb) mutations being associated with idiopathic basal ganglia calcification is also very important in understanding this entity. 7 Further pericyte dysfunction may predispose to breakage of the blood brain barrier and mineralization of lenticulostriate arteries. Whether the lenitculostirate mineralization is the end result of multiple different insults or a homogenous group is not yet clear.…”

“…We do not as yet know which cells are involved in vascular calcification, but there is evidence to implicate pericytes 6 (including unpublished results from the present author) which derive from the mesoderm and have osteogenic properties. 7 Basal ganglia vascular calcification appears to involve adventitial or subendothelial cells, where pericytes are found, 8 and in adults basal ganglia calcification is associated with bone matrix proteins. 9 These observations suggest that pericytes may be responsible for basal ganglia vascular calcification, but much more study is required.…”