Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function
Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-12-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116302273 |
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| author | Arezu Jahani-Asl Cheng Cheng Chi Zhang Azad Bonni |
| author_facet | Arezu Jahani-Asl Cheng Cheng Chi Zhang Azad Bonni |
| author_sort | Arezu Jahani-Asl |
| collection | DOAJ |
| description | Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability. Recent studies have uncovered mechanisms by which mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). PHF6 plays a critical role in the migration of neurons in the mouse cerebral cortex in vivo, and patient-specific mutations disrupt the ability of PHF6 to promote neuronal migration. Interestingly, PHF6 physically associates with the PAF1 transcriptional elongation complex and thereby drives neuronal migration in the cerebral cortex. PHF6 also interacts with the NuRD chromatin remodeling complex and with the nucleolar transcriptional regulator UBF, though the biological role of these interactions remains to be characterized. In other studies, PHF6 mRNA has been identified as the target of the microRNA miR-128 in the cerebral cortex, providing new insights into regulation of PHF6 function in neuronal migration. Importantly, deregulation of PHF6 function in neuronal migration triggers the formation of white matter heterotopias that harbor neuronal hyperexcitability, which may be relevant to the pathogenesis of intellectual disability and seizures in BFLS. Collectively, these studies are beginning to provide key insights into the molecular pathogenesis of BFLS. |
| first_indexed | 2024-12-19T00:46:30Z |
| format | Article |
| id | doaj.art-acfc230aab394896ad4789fa6c5138de |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T00:46:30Z |
| publishDate | 2016-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-acfc230aab394896ad4789fa6c5138de2022-12-21T20:44:15ZengElsevierNeurobiology of Disease1095-953X2016-12-0196227235Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 functionArezu Jahani-Asl0Cheng Cheng1Chi Zhang2Azad Bonni3Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA; Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaDepartment of Neuroscience, Washington University School of Medicine, St Louis, MO, USADepartment of Neuroscience, Washington University School of Medicine, St Louis, MO, USADepartment of Neuroscience, Washington University School of Medicine, St Louis, MO, USA; Corresponding author.Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability. Recent studies have uncovered mechanisms by which mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). PHF6 plays a critical role in the migration of neurons in the mouse cerebral cortex in vivo, and patient-specific mutations disrupt the ability of PHF6 to promote neuronal migration. Interestingly, PHF6 physically associates with the PAF1 transcriptional elongation complex and thereby drives neuronal migration in the cerebral cortex. PHF6 also interacts with the NuRD chromatin remodeling complex and with the nucleolar transcriptional regulator UBF, though the biological role of these interactions remains to be characterized. In other studies, PHF6 mRNA has been identified as the target of the microRNA miR-128 in the cerebral cortex, providing new insights into regulation of PHF6 function in neuronal migration. Importantly, deregulation of PHF6 function in neuronal migration triggers the formation of white matter heterotopias that harbor neuronal hyperexcitability, which may be relevant to the pathogenesis of intellectual disability and seizures in BFLS. Collectively, these studies are beginning to provide key insights into the molecular pathogenesis of BFLS.http://www.sciencedirect.com/science/article/pii/S0969996116302273X-linked intellectual disabilityBörjeson-Forssman-Lehmann syndromePHF6PAF1 complexNeuronal positioningTranscription |
| spellingShingle | Arezu Jahani-Asl Cheng Cheng Chi Zhang Azad Bonni Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function Neurobiology of Disease X-linked intellectual disability Börjeson-Forssman-Lehmann syndrome PHF6 PAF1 complex Neuronal positioning Transcription |
| title | Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function |
| title_full | Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function |
| title_fullStr | Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function |
| title_full_unstemmed | Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function |
| title_short | Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function |
| title_sort | pathogenesis of borjeson forssman lehmann syndrome insights from phf6 function |
| topic | X-linked intellectual disability Börjeson-Forssman-Lehmann syndrome PHF6 PAF1 complex Neuronal positioning Transcription |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116302273 |
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