Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders.
ADCY5
Chorea
PDE10A
Striatal medium spiny neurons
cAMP
Journal
Parkinsonism & related disorders
ISSN: 1873-5126
Titre abrégé: Parkinsonism Relat Disord
Pays: England
ID NLM: 9513583
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
25
11
2022
revised:
08
02
2023
accepted:
10
02
2023
pubmed:
23
2
2023
medline:
8
3
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36805523
pii: S1353-8020(23)00046-9
doi: 10.1016/j.parkreldis.2023.105323
pii:
doi:
Substances chimiques
Phosphoric Diester Hydrolases
EC 3.1.4.-
PDE10A protein, human
EC 3.1.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105323Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors report no competing or conflict of interests.