SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia.

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.

Differential regional gene expression from cardiac dyssynchrony induced by chronic right ventricular free wall pacing in the mouse.

Routine clinical right ventricular pacing generates left ventricular dyssynchrony manifested by early septal shortening followed by late lateral contraction, which, in turn, reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechanoenergetics and worsens clinical prognosis, yet little is known about its molecular consequences. Here, we report the influence of cardiac dyssynchrony on regional cardiac gene expression in mice. Mice were implanted with a custom-designed miniature cardiac pacemaker and subjected to 1-wk overdrive right ventricular free wall pacing (720 beats/min, baseline heart rate 520-620 beats/min) to generate dyssynchrony (pacemaker: 3-V lithium battery, rate programmable, 1.5 g, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler and dyssynchrony by echocardiography. Gene expression from the left ventricular septal and lateral wall myocardium was assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to four synchronously contracting controls. Of the 22,000 genes surveyed, only 18 genes displayed significant (P < 0.01) differential expression between septal/lateral walls >1.5 times that in synchronous controls. Gene changes were confirmed by quantitative PCR with excellent correlations. Most of the genes (n = 16) showed greater septal expression. Of particular interest were seven genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One week of iatrogenic cardiac dyssynchrony triggered regional differential expression in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart.