Dataset Information

Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.

ABSTRACT: BACKGROUND: Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function. OBJECTIVE: To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X-inactivation testing in the mothers of these individuals. RESULTS: 25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A-->G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X-inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (> or =70%) X-inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing. CONCLUSIONS: The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X-inactivation is found in the mother.

SUBMITTER: Crawford J

PROVIDER: S-EPMC2563250 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.

Crawford J J Lower K M KM Hennekam R C M RC Van Esch H H Mégarbané A A Lynch S A SA Turner G G Gécz J J

Journal of medical genetics 20050701 3

<h4>Background</h4>Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function.<h4>Objective</h4>To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X-inactivation testing in the mothers of these individuals.<h4>Results</h4>25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, ...[more]

PMID: 15994862

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Project 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.

Dataset Information

Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.

Publications

Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.

Similar Datasets

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