XPR1: a Gene Linked to Primary Familial Brain Calcification Might Help Explain a Spectrum of Neuropsychiatric Disorders

Abstract

Primary familial brain calcifications (PFBC) compose a rare neurologic condition characterized by a bilateral pattern of hydroxyapatite deposits in basal ganglia, dentate nuclei, and thalamus. PFBC is identified through neuroimaging screenings such as computerized tomography. Patients with PFBC might present a wide variety of neurological symptoms such as mental and motor impairments, often misdiagnosed as Parkinson's disease, schizophrenia, Alzheimer's disease, and migraine. Four genes were confirmed as causative of PFBC: SLC20A2, PDGFB, PDGFRB, and XPR1. Curiously, other studies made occasional links between XPR1 variations or expression changes, in a few neuropsychiatric models. This letter is an assembly on XPR1 variants and expression change pattern data that were published in recent scientific reports, even before the current connection between that gene and brain calcification.

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures

“…Moreover, p.Arg1139Trp is a non-conservative amino acid substitution; because these residues differ in polarity, charge, and size, the mutation is likely to affect secondary protein structure; the in silico predictors SIFT (Kumar et al., 2009) and PolyPhen2 (Adzhubei et al., 2010) indicate this variant should be pathogenic (Table S1). This subject also harbored a de novo nonsense variant of uncertain significance in the XPR1 gene, in which missense variants have been implicated in late-onset primary familial brain calcification (PFBC) (Anheim et al, 2016; Legati et al, 2015; Moura and Oliveira, 2015). Subject 10 had congenital, not late-onset, disease, but only time will tell if she develops PFBC later in life.…”

A Case of Primary Hypoparathyroidism Presenting with Acute Kidney Injury Secondary to Rhabdomyolysis

“…Symmetric calcification of the basal ganglia identified radiographically occurs in a variety of familial and nonfamilial conditions. Primary Familial Brain Calcifications (PFBC), which were known by many names previously, including Fahr disease and striopallidodentate calcinosis, are a genetic disease characterized by various mutations in four separate genes and autosomal dominant inheritance [ 1 – 4 ]. PFBC may present with various psychiatric and neurological symptoms [ 5 ].…”

Idiopathic basal ganglia calcification (Fahr's disease) and dementia

“…Ukai and Kosaka have raised concerns that there might be occult DNTC among patients previously reported as having ‘Fahr's disease with dementia.’ Taken together, these findings indicate possibilities that the pathomechanisms of DNTC, at least in part, might be associated with the specific dysfunction caused by the genetic defects of familial IBGC. In this context, it is noteworthy that the XPR1 gene variants or expression changes are associated with phenotypes observed in schizophrenia, Alzheimer's disease, and amyotrophic lateral sclerosis/frontotemporal lobar degeneration . Further investigations are required to elucidate the possible involvement of the genetic abnormalities of familial IBGC into the pathomechanisms of DNTC, which might shed light on the clinicopathological diversity of DNTC.…”

“…In this context, it is noteworthy that the XPR1 gene variants or expression changes are associated with phenotypes observed in schizophrenia, Alzheimer's disease, and amyotrophic lateral sclerosis/frontotemporal lobar degeneration. 8 Further investigations are required to elucidate the possible involvement of the genetic abnormalities of familial…”