Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function

Neurobiol Dis. 2016 Dec:96:227-235. doi: 10.1016/j.nbd.2016.09.011. Epub 2016 Sep 12.


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.

Keywords: Börjeson-Forssman-Lehmann syndrome; Heterotopia; Neuronal positioning; PAF1 complex; PHF6; Transcription; X-linked intellectual disability.

Publication types

  • Review

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Epilepsy / complications
  • Epilepsy / genetics*
  • Epilepsy / pathology*
  • Face / abnormalities*
  • Face / pathology
  • Fingers / abnormalities*
  • Fingers / pathology
  • Growth Disorders / complications
  • Growth Disorders / genetics*
  • Growth Disorders / pathology*
  • Humans
  • Hypogonadism / complications
  • Hypogonadism / genetics*
  • Hypogonadism / pathology*
  • Intellectual Disability / etiology
  • Intellectual Disability / genetics
  • Mental Retardation, X-Linked / complications
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / pathology*
  • Mutation / genetics
  • Obesity / complications
  • Obesity / genetics*
  • Obesity / pathology*
  • Repressor Proteins


  • Carrier Proteins
  • PHF6 protein, human
  • Repressor Proteins

Supplementary concepts

  • Borjeson-Forssman-Lehmann syndrome