Abstract |
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.
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Authors | Delphine Simon, Benoit Laloo, Malika Barillot, Thomas Barnetche, Camille Blanchard, Caroline Rooryck, Michèle Marche, Ingrid Burgelin, Isabelle Coupry, Nicolas Chassaing, Brigitte Gilbert-Dussardier, Didier Lacombe, Christophe Grosset, Benoit Arveiler |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 19
Issue 10
Pg. 2015-27
(May 15 2010)
ISSN: 1460-2083 [Electronic] England |
PMID | 20181727
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 3' Untranslated Regions
- MIRN433 microRNA, human
- MicroRNAs
- HDAC6 protein, human
- Histone Deacetylase 6
- Histone Deacetylases
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Topics |
- 3' Untranslated Regions
(genetics)
- Acetylation
- Base Sequence
- Cell Line
- Female
- Fetus
(enzymology, pathology)
- Fibroblasts
(enzymology, pathology)
- Gene Dosage
(genetics)
- Gene Expression Regulation
- Genes, Dominant
(genetics)
- Genetic Diseases, X-Linked
(enzymology, genetics)
- Histone Deacetylase 6
- Histone Deacetylases
(genetics)
- Humans
- Male
- MicroRNAs
(metabolism)
- Molecular Sequence Data
- Mutation
(genetics)
- Osteochondrodysplasias
(enzymology, genetics)
- Pedigree
- RNA Processing, Post-Transcriptional
- RNA Stability
- Sequence Analysis, DNA
- Skin
(pathology)
- Thymus Gland
(enzymology)
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