A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia

Hum Mol Genet. 2010 May 15;19(10):2015-27. doi: 10.1093/hmg/ddq083. Epub 2010 Feb 24.


A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3'-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Acetylation
  • Base Sequence
  • Cell Line
  • Female
  • Fetus / enzymology
  • Fetus / pathology
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Gene Dosage / genetics
  • Gene Expression Regulation*
  • Genes, Dominant / genetics
  • Genetic Diseases, X-Linked / enzymology*
  • Genetic Diseases, X-Linked / genetics
  • Histone Deacetylase 6
  • Histone Deacetylases / genetics*
  • Humans
  • Male
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Osteochondrodysplasias / enzymology*
  • Osteochondrodysplasias / genetics
  • Pedigree
  • RNA Processing, Post-Transcriptional
  • RNA Stability
  • Sequence Analysis, DNA
  • Skin / pathology
  • Thymus Gland / enzymology


  • 3' Untranslated Regions
  • MIRN433 microRNA, human
  • MicroRNAs
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases