HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain

Hum Mol Genet. 2015 Jun 15;24(12):3335-47. doi: 10.1093/hmg/ddv083. Epub 2015 Mar 3.


Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene MMACHC, which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Brain / cytology*
  • Brain / embryology
  • Carrier Proteins / genetics
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Gene Expression
  • HEK293 Cells
  • Host Cell Factor C1 / chemistry
  • Host Cell Factor C1 / genetics*
  • Host Cell Factor C1 / metabolism
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Mice
  • Mutation*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Oxidoreductases
  • Pedigree
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Transduction, Genetic


  • Carrier Proteins
  • Host Cell Factor C1
  • RNA, Small Interfering
  • MMACHC protein, human
  • Oxidoreductases