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
Identifieur interne : 001B10 ( Main/Exploration ); précédent : 001B09; suivant : 001B11A 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
Auteurs : Delphine Simon ; Benoit Laloo ; Malika Barillot ; Thomas Barnetche ; Camille Blanchard ; Caroline Rooryck ; Michle Marche ; Ingrid Burgelin ; Isabelle Coupry ; Nicolas Chassaing [France] ; Brigitte Gilbert-Dussardier [France] ; Didier Lacombe ; Christophe Grosset ; Benoit Arveiler [France]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-05-15.
Abstract
A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3q13.1. 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 -tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated -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.
Url:
DOI: 10.1093/hmg/ddq083
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unit="issue">10</biblScope><biblScope unit="page" from="2015">2015</biblScope><biblScope unit="page" to="2027">2027</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">0541830B1CA0EC6C7C9090B76EB19A6E661F7870</idno><idno type="DOI">10.1093/hmg/ddq083</idno><idno type="ArticleID">ddq083</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3q13.1. 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 -tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated -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.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Midi-Pyrénées</li><li>Nouvelle-Aquitaine</li><li>Occitanie (région administrative)</li><li>Poitou-Charentes</li></region></list><tree><noCountry><name sortKey="Barillot, Malika" sort="Barillot, Malika" uniqKey="Barillot M" first="Malika" last="Barillot">Malika Barillot</name><name sortKey="Barnetche, Thomas" sort="Barnetche, Thomas" uniqKey="Barnetche T" first="Thomas" last="Barnetche">Thomas Barnetche</name><name sortKey="Blanchard, Camille" sort="Blanchard, Camille" uniqKey="Blanchard C" first="Camille" last="Blanchard">Camille Blanchard</name><name sortKey="Burgelin, Ingrid" sort="Burgelin, Ingrid" uniqKey="Burgelin I" first="Ingrid" last="Burgelin">Ingrid Burgelin</name><name sortKey="Coupry, Isabelle" sort="Coupry, Isabelle" uniqKey="Coupry I" first="Isabelle" last="Coupry">Isabelle Coupry</name><name sortKey="Grosset, Christophe" sort="Grosset, Christophe" uniqKey="Grosset C" first="Christophe" last="Grosset">Christophe Grosset</name><name sortKey="Lacombe, Didier" sort="Lacombe, Didier" uniqKey="Lacombe D" first="Didier" last="Lacombe">Didier Lacombe</name><name sortKey="Laloo, Benoit" sort="Laloo, Benoit" uniqKey="Laloo B" first="Benoit" last="Laloo">Benoit Laloo</name><name sortKey="Marche, Michle" sort="Marche, Michle" uniqKey="Marche M" first="Michle" last="Marche">Michle Marche</name><name sortKey="Rooryck, Caroline" sort="Rooryck, Caroline" uniqKey="Rooryck C" first="Caroline" last="Rooryck">Caroline Rooryck</name><name sortKey="Simon, Delphine" sort="Simon, Delphine" uniqKey="Simon D" first="Delphine" last="Simon">Delphine Simon</name></noCountry><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Chassaing, Nicolas" sort="Chassaing, Nicolas" uniqKey="Chassaing N" first="Nicolas" last="Chassaing">Nicolas Chassaing</name></region><name sortKey="Arveiler, Benoit" sort="Arveiler, Benoit" uniqKey="Arveiler B" first="Benoit" last="Arveiler">Benoit Arveiler</name><name sortKey="Gilbert Dussardier, Brigitte" sort="Gilbert Dussardier, Brigitte" uniqKey="Gilbert Dussardier B" first="Brigitte" last="Gilbert-Dussardier">Brigitte Gilbert-Dussardier</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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