title: 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.
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.
authors.affiliation: Laboratoire de Génétique Humaine, EA 4137, Université Victor Segalen Bordeaux 2, Bordeaux 33076, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Simon
authors.forename: Benoit
authors.initials: B
authors.lastname: Laloo
authors.forename: Malika
authors.initials: M
authors.lastname: Barillot
authors.forename: Thomas
authors.initials: T
authors.lastname: Barnetche
authors.forename: Camille
authors.initials: C
authors.lastname: Blanchard
authors.forename: Caroline
authors.initials: C
authors.lastname: Rooryck
authors.forename: Michèle
authors.initials: M
authors.lastname: Marche
authors.forename: Ingrid
authors.initials: I
authors.lastname: Burgelin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Christophe
authors.initials: C
authors.lastname: Grosset
authors.forename: Benoit
authors.initials: B
authors.lastname: Arveiler
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000107:Acetylation; D001483:Base Sequence; D002460:Cell Line; D005260:Female; D005333:Fetus / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D018628:Gene Dosage / Q000235:genetics; D005786:Gene Expression Regulation; D005799:Genes, Dominant / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000201:enzymology* / Q000235:genetics; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000201:enzymology* / Q000235:genetics; D010375:Pedigree; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology; D013950:Thymus Gland / Q000201:enzymology
chemical_list: D020413:3' Untranslated Regions; C548883:MIRN433 microRNA, human; D035683:MicroRNAs; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases