PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development
<p dir="ltr">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...
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| مؤلفون آخرون: | , , , , , , , , |
| منشور في: |
2020
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| الموضوعات: | |
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| _version_ | 1864513516144164864 |
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| author | Sahar I. Da’as (9631717) |
| author2 | Waleed Aamer (14056969) Waseem Hasan (17280670) Aljazi Al-Maraghi (14056975) Alya Al-Kurbi (18543970) Houda Kilani (18543973) Jehan AlRayahi (17346976) Khaled Zamel (17563101) Mitchell A. Stotland (15220174) Khalid A. Fakhro (3158862) |
| author2_role | author author author author author author author author author |
| author_facet | Sahar I. Da’as (9631717) Waleed Aamer (14056969) Waseem Hasan (17280670) Aljazi Al-Maraghi (14056975) Alya Al-Kurbi (18543970) Houda Kilani (18543973) Jehan AlRayahi (17346976) Khaled Zamel (17563101) Mitchell A. Stotland (15220174) Khalid A. Fakhro (3158862) |
| author_role | author |
| dc.creator.none.fl_str_mv | Sahar I. Da’as (9631717) Waleed Aamer (14056969) Waseem Hasan (17280670) Aljazi Al-Maraghi (14056975) Alya Al-Kurbi (18543970) Houda Kilani (18543973) Jehan AlRayahi (17346976) Khaled Zamel (17563101) Mitchell A. Stotland (15220174) Khalid A. Fakhro (3158862) |
| dc.date.none.fl_str_mv | 2020-07-27T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/cells9081782 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/PGAP3_Associated_with_Hyperphosphatasia_with_Mental_Retardation_Plays_a_Novel_Role_in_Brain_Morphogenesis_and_Neuronal_Wiring_at_Early_Development/25808311 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Neurosciences hyperphosphatasia mental retardation syndrome 4 (HPMRS4) post-GPI attachment to proteins 3 (PGAP3) neurological disorder human disease model zebrafish neural tube defect whole genome sequencing |
| dc.title.none.fl_str_mv | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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’s novel role in brain morphogenesis and neuronal wiring.</p><h2>Other Information</h2><p dir="ltr">Published in: Cells<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/cells9081782" target="_blank">https://dx.doi.org/10.3390/cells9081782</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_fdd6de1940c0f9668eaaa5c24dd1a623 |
| identifier_str_mv | 10.3390/cells9081782 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25808311 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early DevelopmentSahar I. Da’as (9631717)Waleed Aamer (14056969)Waseem Hasan (17280670)Aljazi Al-Maraghi (14056975)Alya Al-Kurbi (18543970)Houda Kilani (18543973)Jehan AlRayahi (17346976)Khaled Zamel (17563101)Mitchell A. Stotland (15220174)Khalid A. Fakhro (3158862)Biological sciencesGeneticsBiomedical and clinical sciencesNeuroscienceshyperphosphatasia mental retardation syndrome 4 (HPMRS4)post-GPI attachment to proteins 3 (PGAP3)neurological disorderhuman disease modelzebrafishneural tube defectwhole genome sequencing<p dir="ltr">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’s novel role in brain morphogenesis and neuronal wiring.</p><h2>Other Information</h2><p dir="ltr">Published in: Cells<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/cells9081782" target="_blank">https://dx.doi.org/10.3390/cells9081782</a></p>2020-07-27T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/cells9081782https://figshare.com/articles/journal_contribution/PGAP3_Associated_with_Hyperphosphatasia_with_Mental_Retardation_Plays_a_Novel_Role_in_Brain_Morphogenesis_and_Neuronal_Wiring_at_Early_Development/25808311CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258083112020-07-27T06:00:00Z |
| spellingShingle | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development Sahar I. Da’as (9631717) Biological sciences Genetics Biomedical and clinical sciences Neurosciences hyperphosphatasia mental retardation syndrome 4 (HPMRS4) post-GPI attachment to proteins 3 (PGAP3) neurological disorder human disease model zebrafish neural tube defect whole genome sequencing |
| status_str | publishedVersion |
| title | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| title_full | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| title_fullStr | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| title_full_unstemmed | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| title_short | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| title_sort | PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development |
| topic | Biological sciences Genetics Biomedical and clinical sciences Neurosciences hyperphosphatasia mental retardation syndrome 4 (HPMRS4) post-GPI attachment to proteins 3 (PGAP3) neurological disorder human disease model zebrafish neural tube defect whole genome sequencing |