en
Scientific article
Open access
English

Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations

Published inNature communications, vol. 12, no. 1, 5013
Publication date2021-08-18
First online date2021-08-18
Abstract

Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in- cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.

eng
Funding
Citation (ISO format)
BOLT, Christopher Chase et al. Mesomelic dysplasias associated with the <i>HOXD</i> locus are caused by regulatory reallocations. In: Nature communications, 2021, vol. 12, n° 1, p. 5013. doi: 10.1038/s41467-021-25330-y
Main files (1)
Article (Published version)
Identifiers
ISSN of the journal2041-1723
7views
2downloads

Technical informations

Creation03/24/2024 9:38:56 AM
First validation04/22/2024 12:41:03 PM
Update time04/22/2024 12:41:03 PM
Status update04/22/2024 12:41:03 PM
Last indexation05/06/2024 6:26:25 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack