Abstract
The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.
Highlights
Dystonias are rare movement disorders characterised by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures
The first dopamine-related gene identified for dystonia was GCH1, encoding the rate-limiting enzyme in the pathway that converts guanosine triphosphate (GTP) to tetrahydrobiopterin (BH4) [3], which is an essential cofactor for dopamine biosynthesis (Fig. 2A)
A recent large study focusing on neurodevelopmental disorders with dystonia raised attention to inosine monophosphate dehydrogenase 2 (IMPDH2) as a candidate gene [9], but direct evidence has been lacking
Summary
Dystonias are rare movement disorders characterised by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Dystonia can manifest as an isolated symptom or combined with e.g. parkinsonism or myoclonus [1]. While many pathogenic pathways are associated with dystonia, dopamine signalling is a commonly altered one [reviewed in [2]]. The first dopamine-related gene identified for dystonia was GCH1, encoding the rate-limiting enzyme in the pathway that converts guanosine triphosphate (GTP) to tetrahydrobiopterin (BH4) [3], which is an essential cofactor for dopamine biosynthesis (Fig. 2A). Heterozygous GCH1 variants decrease dopamine synthesis in nigrostriatal neurons, leading to childhood-onset, progressive, dopa-responsive dystonia [4]. Variants in HPRT1, another purine metabolic enzyme, result in generalised dystonia with neuro-behavioural manifestations [5]. Next-generation sequencing has uncovered numerous novel dystonia genes, furthering mechanistic knowledge. We report inosine monophosphate dehydrogenase 2 (IMPDH2) as a novel gene for autosomal dominantly inherited dystonia
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