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

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

doi:10.1016/j.parkreldis.2023.105323

Cited by 2 publications

(5 citation statements)

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“…Variants that modify the shape, size, or electrostatic properties of such a site may weaken or abolish this interaction. For example, the Phe300Leu variant in PDE10A substitutes a large hydrophobic amino acid in the binding site with a smaller one, preventing the interaction with cAMP (Bohlega et al., 2023).…”

Section: Guidelines For Understanding Resultsmentioning

confidence: 99%

Leveraging AI Advances and Online Tools for Structure‐Based Variant Analysis

et al. 2023

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Understanding how a gene variant affects protein function is important in life science, as it helps explain traits or dysfunctions in organisms. In a clinical setting, this understanding makes it possible to improve and personalize patient care. Bioinformatic tools often only assign a pathogenicity score, rather than providing information about the molecular basis for phenotypes. Experimental testing can furnish this information, but this is slow and costly and requires expertise and equipment not available in a clinical setting. Conversely, mapping a gene variant onto the three‐dimensional (3D) protein structure provides a fast molecular assessment free of charge. Before 2021, this type of analysis was severely limited by the availability of experimentally determined 3D protein structures. Advances in artificial intelligence algorithms now allow confident prediction of protein structural features from sequence alone. The aim of the protocols presented here is to enable non‐experts to use databases and online tools to investigate the molecular effect of a genetic variant. The Basic Protocol relies only on the online resources AlphaFold, Protein Structure Database, and UniProt. Alternate Protocols document the usage of the Protein Data Bank, SWISS‐MODEL, ColabFold, and PyMOL for structure‐based variant analysis. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.Basic Protocol: 3D Mapping based on UniProt and AlphaFoldAlternate Protocol 1: Using experimental models from the PDBAlternate Protocol 2: Using information from homology modeling with SWISS‐MODELAlternate Protocol 3: Predicting 3D structures with ColabFoldAlternate Protocol 4: Structure visualization and analysis with PyMOL

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Section: Guidelines For Understanding Resultsmentioning

confidence: 99%

Leveraging AI Advances and Online Tools for Structure‐Based Variant Analysis

et al. 2023

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“…However, there has been recently reported an Arab family with five affected members carrying a homozygous mutation in GAF-B domain exhibiting a more severe phenotype resembling GAF-A mutations (21). Diurnal fluctuation of choreatic movements (chorea being more severe in the morning) were reported in only few patients (14,21). Few patients with mutations in GAF-B domain also exhibited limb dystonia (14,21).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Diurnal fluctuation of choreatic movements (chorea being more severe in the morning) were reported in only few patients (14,21). Few patients with mutations in GAF-B domain also exhibited limb dystonia (14,21).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…21 Diurnal fluctuation of choreatic movements (chorea being more severe in the morning) were reported in only few patients. 14,21 Few patients with mutations in GAF-B domain also exhibited limb dystonia. 14,21 On a molecular level, GAF-B mutations probably alter the morphology of cAMP deep binding pocket, where cAMP is bound and activates the wild-type enzyme.…”

Section: Mutations In Gaf-b Domainmentioning

confidence: 99%

“…14,21 Few patients with mutations in GAF-B domain also exhibited limb dystonia. 14,21 On a molecular level, GAF-B mutations probably alter the morphology of cAMP deep binding pocket, where cAMP is bound and activates the wild-type enzyme. 22 Mencacci and colleagues reported that p.F300L and p.F334L mutations did not affect the basal activity of the enzyme; however, they inhibited the cAMP-stimulatory effect for cGMP hydrolysis.…”

Section: Mutations In Gaf-b Domainmentioning

confidence: 99%

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PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases

Kalampokini,

Xiromerisiou,

Bargiotas

et al. 2024

Neuropediatrics

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Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which act as intracellular second messengers for signal transduction pathways and modulate various processes in the central nervous system. Recent discoveries that mutations in genes encoding different PDEs, including PDE10A, are responsible for rare forms of chorea in children led to the recognition of an emerging role of PDEs in the field of pediatric movement disorders. A comprehensive literature review of all reported cases of PDE10A mutations in PubMed and Web of science was performed in English. We included 8 studies, describing 31 patients harboring a PDE10A mutation and exhibiting a hyperkinetic movement disorder with onset in infancy or childhood. Mutations in both GAF-A, GAF-B regulatory domains as well as outside the GAF domains of the PDE10A gene have been reported to cause hyperkinetic movement disorders. In general, patients with homozygous mutations in either GAF-A domain of PDE10A present with a more severe phenotype and at an earlier age but without any extensive abnormalities of the striata compared to patients with dominant variants in GAF-B domain, indicating that dominant and recessive mutations have different pathogenic mechanisms. PDE10A plays a key role in regulating control of striato-cortical movement. Comprehension of the molecular mechanisms within the cAMP and cGMP signaling systems caused by PDE10A mutations may inform novel therapeutic strategies that could alleviate symptoms in young patients affected by these rare movement disorders.

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

Cited by 2 publications

References 11 publications

Leveraging AI Advances and Online Tools for Structure‐Based Variant Analysis

Leveraging AI Advances and Online Tools for Structure‐Based Variant Analysis

PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases

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