Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders

Saeed Bohlega*, Ali H. Abusrair, Zainah Al-Qahtani, Francisco J. Guzmán-Vega, Reshmi Ramakrishnan, Haya Aldosari, Amaal Aldakheel, Salma Al-Qahtani, Dorota Monies, Stefan T. Arold

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifest with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development, with striatal lesions. Methods: Phenotypic characteristics of affected individuals with PDE10A mutations belonging to a single family were recorded. In addition, Sanger sequencing and in silico analysis were used to identify the mutations. Homozygosity mapping was applied together with whole exome sequencing. Results: Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed a bi-allelic GAF-B mutation (c.883G > A:p. D295 N; p.Asp295Asn) that was segregated with all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia, with normal brain MRI. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity likely phenocopies GAF-A mutations, and this is achieved through a distinct mechanism. Conclusions: Collectively, our findings demonstrate the association of recessive and dominant phenotypes of known variants, and further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.

Original languageEnglish (US)
Article number105323
JournalParkinsonism and Related Disorders
StatePublished - Mar 2023


  • ADCY5
  • cAMP
  • Chorea
  • PDE10A
  • Striatal medium spiny neurons

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology


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