IMPDH2: a new gene associated with dominant juvenile-onset dystonia-tremor disorder.
Anna KuukasjärviJuan C LandoniJyrki KaukonenMika JuhakoskiMari AuranenTommi TorkkeliVidya VelagapudiAnu SuomalainenPublished in: European journal of human genetics : EJHG (2021)
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.
Keyphrases
- deep brain stimulation
- early onset
- parkinson disease
- copy number
- genome wide
- genome wide identification
- depressive symptoms
- induced apoptosis
- uric acid
- dna methylation
- cell death
- gene expression
- young adults
- endoplasmic reticulum stress
- genome wide analysis
- prefrontal cortex
- transcription factor
- pi k akt
- childhood cancer