Dataset Information

PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females.

ABSTRACT: In a 16-year-old girl with intellectual disability, irregular teeth, slight body asymmetry, and striated skin pigmentation, highly skewed X-inactivation increased the likelihood of an X-linked cause of her condition. Among these, prominent supraorbital ridges and hearing loss suggested a filaminopathy, but no filamin A mutation was found. The correct diagnosis, Borjeson-Forssman-Lehmann syndrome (BFLS, MIM#301900), was first made when a copy number array identified a de novo 15-kb deletion of the terminal 3 exons of the PHF6 gene. In retrospect, her phenotype resembled that of males with BFLS. Such deletions of PHF6 have not been reported previously. This might be because PHF6 mutations are rarely looked for in females since classical BFLS so far has been thought to be a male-specific syndrome, and large PHF6 deletions might be incompatible with male fetal survival. If this is the case, sporadic BFLS could be more frequent in females than in males.

SUBMITTER: Berland S

PROVIDER: S-EPMC3214959 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females.

Berland S S Alme K K Brendehaug A A Houge G G Hovland R R

Molecular syndromology 20110719 6

In a 16-year-old girl with intellectual disability, irregular teeth, slight body asymmetry, and striated skin pigmentation, highly skewed X-inactivation increased the likelihood of an X-linked cause of her condition. Among these, prominent supraorbital ridges and hearing loss suggested a filaminopathy, but no filamin A mutation was found. The correct diagnosis, Borjeson-Forssman-Lehmann syndrome (BFLS, MIM#301900), was first made when a copy number array identified a de novo 15-kb deletion of th ...[more]

PMID: 22190899

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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

PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females.

Publications

PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females.

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