A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability

Am J Hum Genet. 2012 Oct 5;91(4):694-702. doi: 10.1016/j.ajhg.2012.08.011. Epub 2012 Sep 20.


The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Astrocytes / metabolism
  • Binding Sites
  • Chromatin / genetics
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease
  • Host Cell Factor C1 / genetics*
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mental Retardation, X-Linked / genetics
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • RNA, Untranslated / genetics*
  • Transcription Factors / genetics
  • X Chromosome / genetics
  • YY1 Transcription Factor / genetics


  • Chromatin
  • HCFC1 protein, human
  • Hcfc1 protein, mouse
  • Host Cell Factor C1
  • RNA, Untranslated
  • Transcription Factors
  • YY1 Transcription Factor
  • Yy1 protein, mouse

Supplementary concepts

  • Mental Retardation, X-Linked 3