Early-Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Phosphodiesterase 1B (PDE1B) and PDE10A regulate cyclic nucleotide levels in basal ganglia, crucial for motor control.
• Loss-of-function variants in PDE10A are linked to hyperkinetic movement disorders.
• The role of PDE1B in human disease was previously uncharacterized.

Purpose of the Study:

• To identify and characterize a novel autosomal recessive movement disorder.
• To investigate the molecular basis of this disorder caused by biallelic PDE1B variants.

Main Methods:

• Clinical assessment by geneticists and neurologists.
• Whole exome sequencing and Sanger sequencing for variant identification and segregation.
• In vitro functional studies including mini-gene splicing assays and protein analysis in HEK293 cells.

Main Results:

• Seven individuals from five families presented with hypotonia, ataxia, dystonia, developmental delay, and intellectual disability.
• Biallelic PDE1B variants, including truncating and splicing mutations, were identified in all affected individuals.
• Functional studies confirmed loss of PDE1B catalytic activity due to these variants, establishing causality.

Conclusions:

• Biallelic loss-of-function variants in PDE1B cause a novel early-onset movement disorder.
• The phenotype associated with PDE1B deficiency resembles that of PDE10A deficiency.
• This study elucidates the genetic basis of a new rare movement disorder.