Objective: Identification and functional analysis of the disease-causing gene in a family with dominantly inherited cervical dystonia.

Background: With the introduction of next generation sequencing in clinical diagnostics there is an increase in findings of potential candidate variants. However, the causal relationship between the novel genes and the disease remains unknown and may even be an incidental finding. It is therefore of utmost importance to perform functional validations before the candidate variants can be used in clinical decision-making. In this study we aim to validate a PANK2 mutation as the disease-causing gene in cervical dystonia with iron accumulation in the basal ganglia.

Methods: Dystonia gene panel sequencing and exome sequencing followed by analysis using bioinformatics was performed in two relatives exhibiting autosomal dominant cervical dystonia (one with progressive myoclonus dystonia phenotype). Functional analysis in cell model systems overexpressing the mutant PanK2 protein and in patient fibroblasts were used to assess the pathogenic effects of the putative dominant candidate variant.

Results: Gene panel sequencing identified a novel heterozygous truncating variant c.444delT;p.Arg440fs*10 in PANK2. Exome sequencing confirmed the mutation and excluded other potential causative variants. Since only recessive PANK2 mutations are known to cause pantothenate kinase-associated neurodegeneration (PKAN), large PANK2 deletions and/or insertions on the other allele were excluded through MLPA. MRI revealed evident iron accumulation in the basal ganglia of affected cases, but to a milder extend than PKAN patients described in literature. Functional studies showed that p.Arg440fs*10 led to aberrant processing of precursor PanK2, a less stable intermediate (i)PanK2 protein, and disrupted the dimerization of iPanK2 in HEK293T cells like the known recessive p.Gly521Arg PANK2 mutation indicative of loss of proper PanK2 kinase function. This coincided with two-fold decreased PanK2 protein levels and two-fold increased iron exporter (FPN) mRNA levels in patient fibroblasts.

Conclusions: Our results point toward a pathogenic effect of p.Arg440fs*10 in PANK2. This suggests a dominant mutation in the PANK2 gene not described before. (Previously presented at ESHG conference in May 27-30, 2017).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-dominant-pank2-mutation-resulting-in-cervical-dystonia-with-iron-accumulation-in-the-basal-ganglia/