PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development
| Autor: | Houda Kilani, Aljazi Al-Maraghi, Sahar I. Da'as, Alya Al-Kurbi, Waleed Aamer, Khalid A. Fakhro, Mitchell A. Stotland, Khaled Zamel, Jehan AlRayahi, Waseem Hasan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Nervous system hyperphosphatasia mental retardation syndrome 4 (HPMRS4) Corpus callosum neural tube defect Article 03 medical and health sciences Dysgenesis 0302 clinical medicine medicine Global developmental delay neurological disorder lcsh:QH301-705.5 Zebrafish Hindbrain formation whole genome sequencing biology post-GPI attachment to proteins 3 (PGAP3) General Medicine biology.organism_classification zebrafish Hypotonia human disease model 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) medicine.symptom Brain morphogenesis Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Cells Volume 9 Issue 8 Cells, Vol 9, Iss 1782, p 1782 (2020) |
| ISSN: | 2073-4409 |
| DOI: | 10.3390/cells9081782 |
| Popis: | 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> 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&rsquo s novel role in brain morphogenesis and neuronal wiring. |
| Databáze: | OpenAIRE |
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