Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster
| العنوان: | Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster |
|---|---|
| المؤلفون: | Richard Redon, Pierre Lindenbaum, Denis Duboule, Flavie Diguet, Annaig Briand, André Mégarbané, Christian Bonnard, Caroline Schluth-Bolard, Cédric Le Caignec, Damien Sanlaville, Marie-Laure Vuillaume, Olivier Pichon, Benoît de Courtivron, Pierre-Antoine Rollat-Farnier, Marta Sanchez-Castro, Annick Toutain |
| المصدر: | Eur J Hum Genet |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, family, translocation, Mesomelic Dysplasia, breakpoints, Locus (genetics), hierarchy, Biology, Article, 03 medical and health sciences, Loss of Function Mutation, Gene Duplication, expression, Gene duplication, Genetics, medicine, Humans, Limb development, Upper Extremity Deformities, Congenital, Enhancer, Gene, domains, time, Cells, Cultured, Genetics (clinical), kantaputra type, Homeodomain Proteins, Bone Diseases, Developmental, 0303 health sciences, 030305 genetics & heredity, Infant, medicine.disease, Phenotype, HOXD13, Dysplasia, Multigene Family, Female |
| الوصف: | The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus. |
| تدمد: | 1476-5438 1018-4813 |
| DOI: | 10.1038/s41431-019-0522-2 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::927109b1dcc8ee33741567a903fbbbe3 https://doi.org/10.1038/s41431-019-0522-2 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....927109b1dcc8ee33741567a903fbbbe3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765438 10184813 |
|---|---|
| DOI: | 10.1038/s41431-019-0522-2 |