{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T06:34:59Z","timestamp":1776407699028,"version":"3.51.2"},"reference-count":26,"publisher":"BMJ","issue":"6","funder":[{"name":"People\u2019s Hospital School Construction Project","award":["BMU2023XY016"],"award-info":[{"award-number":["BMU2023XY016"]}]},{"name":"Peking University People\u2019s Hospital R&D Fund Unveiling Project","award":["RDGS2023-10"],"award-info":[{"award-number":["RDGS2023-10"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171436"],"award-info":[{"award-number":["82171436"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Health Promotion Research Fund Project","award":["2020-2-4077"],"award-info":[{"award-number":["2020-2-4077"]}]},{"name":"Beijing Clinical Key Specialty Construction Project","award":["2199000726"],"award-info":[{"award-number":["2199000726"]}]},{"name":"Peking University People\u2019s Hospital Talent Introduction Start-up Fund","award":["2023-T-02"],"award-info":[{"award-number":["2023-T-02"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,1,16]]},"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>PHACTR1 (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 <jats:italic>de novo<\/jats:italic> variants in <jats:italic>PHACTR1<\/jats:italic> and analyse the impact of variants on protein\u2013protein interaction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We identified seven patients with <jats:italic>PHACTR1<\/jats:italic> variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype\u2013phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein\u2013protein interactions and interfaces.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Eight individuals carried missense variants and one had CNV in the <jats:italic>PHACTR1<\/jats:italic>. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of <jats:italic>PHACTR1<\/jats:italic>. 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\u2013PPP1CA or PHACTR1\u2013G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Patients with variants in <jats:italic>PHACTR1<\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109638","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T13:20:27Z","timestamp":1706188827000},"page":"536-542","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Genotype and phenotype correlation of <i>PHACTR1<\/i>-related neurological disorders"],"prefix":"10.1136","volume":"61","author":[{"given":"Zhao","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Peking University People's Hospital, Beijing, China"},{"name":"Epilepsy Center, Peking University People's Hospital, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynette","family":"Sadleir","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Himanshu","family":"Goel","sequence":"additional","affiliation":[{"name":"Hunter Genetics, Waratah, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianru","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People's Hospital, Beijing, China"},{"name":"Epilepsy Center, Peking University People's Hospital, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People's Hospital, Beijing, China"},{"name":"Epilepsy Center, Peking University People's Hospital, Beijing, 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