Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells

Neuroscience. 2018 Feb 1;370:170-180. doi: 10.1016/j.neuroscience.2017.05.031. Epub 2017 May 29.


Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. However, the molecular consequences of reduced PHF21A expression remain elusive. In this study, we analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated. The patient cells displayed down-regulation of key pathways relevant to learning and memory, including Cyclic Adenosine Monophosphate (cAMP)-signaling pathway genes. We found that PHF21A is required for full induction of a luciferase reporter carrying cAMP-responsive elements (CRE) following stimulation by the cAMP analog, forskolin. Finally, PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation. These results suggest that an impaired response to cAMP signaling might be involved in the pathology of PHF21A deficiency. This article is part of a Special Issue entitled: [SI: Molecules & Cognition].

Keywords: Potocki–Shaffer Syndrome; RNA-Sequencing; cAMP signaling; chromatin; histone methylation; neurodevelopmental disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromosome Deletion
  • Chromosome Disorders / metabolism
  • Chromosomes, Human, Pair 11 / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism*
  • Exostoses, Multiple Hereditary / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Histone Deacetylases / deficiency*
  • Histone Deacetylases / genetics
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • RNA, Small Interfering
  • Transcription, Genetic


  • RNA, Small Interfering
  • Colforsin
  • Cyclic AMP
  • PHF21A protein, human
  • Histone Deacetylases

Supplementary concepts

  • Potocki-Shaffer syndrome

Associated data

  • GEO/GSE94587