Genotype and phenotype correlation of PHACTR1-related neurological disorders

• Published in: Journal of medical genetics Vol. 61; no. 6; pp. 536 - 542
• Main Authors: Xu, Zhao, Sadleir, Lynette, Goel, Himanshu, Jiao, Xianru, Niu, Yue, Zhou, Zongpu, de Valles-Ibáñez, Guillem, Poke, Gemma, Hildebrand, Michael, Lieffering, Nico, Qin, Jiong, Yang, Zhixian
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.06.2024; BMJ Publishing Group LTD
• Subjects: Actin; Actins - genetics; Age; Child; Child, Preschool; Convulsions & seizures; Drug resistance; Encephalopathy; Epilepsy; Exome Sequencing; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetics, Medical; Genotype; Genotype & phenotype; Genotype-phenotype correlations; Genotypes; Humans; Infant; Interfaces; Male; Metabolism; Microfilament Proteins - genetics; Mutation, Missense - genetics; Nervous System Diseases - genetics; Neurological diseases; Neurological disorders; Neurology; Patients; Pediatrics; Phenotype; Phenotypes; Phosphatase; Protein interaction; Protein Phosphatase 1 - genetics; Proteins; Seizures; Spasms, Infantile - genetics; New York; United States > US; Neurology; Pediatrics; Genotype; Genetics, Medical; Epilepsy
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg-2023-109638

BackgroundPHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein–protein interaction.MethodsWe identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype–phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein–protein interactions and interfaces.ResultsEight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1–PPP1CA or PHACTR1–G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain).ConclusionsPatients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.