{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T10:05:09Z","timestamp":1774519509739,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T00:00:00Z","timestamp":1595808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sidra Medicine","award":["IRF-2019, SDR400034"],"award-info":[{"award-number":["IRF-2019, SDR400034"]}]},{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"publisher","award":["NPRP11S-0110-180250"],"award-info":[{"award-number":["NPRP11S-0110-180250"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C&gt;T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene\u2019s novel role in brain morphogenesis and neuronal wiring.<\/jats:p>","DOI":"10.3390\/cells9081782","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T09:24:49Z","timestamp":1595841889000},"page":"1782","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development"],"prefix":"10.3390","volume":"9","author":[{"given":"Sahar I.","family":"Da\u2019as","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-3509","authenticated-orcid":false,"given":"Waleed","family":"Aamer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Waseem","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aljazi","family":"Al-Maraghi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alya","family":"Al-Kurbi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houda","family":"Kilani","sequence":"additional","affiliation":[{"name":"Division of Plastic and Craniofacial Surgery, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3864-6547","authenticated-orcid":false,"given":"Jehan","family":"AlRayahi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled","family":"Zamel","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Sidra Medicine, Doha 26999, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medical College, Doha 24144, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell A.","family":"Stotland","sequence":"additional","affiliation":[{"name":"Division of Plastic and Craniofacial Surgery, Sidra Medicine, Doha 26999, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medical College, Doha 24144, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-1276","authenticated-orcid":false,"given":"Khalid A.","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medical College, Doha 24144, Qatar"},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha 34110, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ajhg.2013.12.012","article-title":"Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation","volume":"94","author":"Howard","year":"2014","journal-title":"Am. 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