Poleg, T., Hadar, N., Kristal, E. et al. (19 more authors) (2025) Early‐Onset Movement Disorder Syndrome Caused by Biallelic Variants in PDE1B Encoding Phosphodiesterase 1B. Movement Disorders. ISSN 0885-3185
Abstract
Background
Breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in basal ganglia cells through hydrolysis of diesteric bonds, primarily by PDE10A and PDE1B, is essential for normal human movement. While biallelic loss-of-function variants in PDE10A are known to cause hyperkinetic movement disorders, the role of PDE1B in human disease has not been characterized.
Objectives
We aimed to define the phenotypic and molecular characteristics of a novel autosomal recessive disorder caused by biallelic PDE1B variants.
Methods
Clinical phenotyping by senior geneticists and neurologists, followed by whole exome sequencing, segregation analysis (Sanger sequencing), and molecular studies, including mini-gene splicing assays and protein studies in transfected HEK293 cells.
Results
Seven affected individuals from five unrelated pedigrees presented with an apparently autosomal recessive disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability. Biallelic PDE1B variants were identified in all affected individuals: three truncating (p.Q45*, p.Q86*, p.S298Afs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C). Functional studies confirmed that the truncating variants caused loss of the catalytic domain, resulting in truncated or absent functional protein. Splicing variants led to exon skipping, frameshifts, and catalytic domain disruption. These findings establish a causative link between biallelic PDE1B variants and the observed clinical phenotype.
Conclusions
Biallelic loss-of-function variants in PDE1B underlie a novel early-onset movement disorder resembling the phenotype associated with PDE10A deficiency. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | PDE1B; movement disorder; phosphodies-terase; exome sequencing; early onset |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Funding Information: | Funder Grant number UKRI (UK Research and Innovation) MR/Y034325/1 Rosetrees Trust A2459 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Jun 2025 12:51 |
Last Modified: | 30 Jun 2025 12:51 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/mds.30249 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:228383 |