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.
Highlights
Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb
Several human mesomelic dysplasias have been associated with the HOXD locus[2,4,25,26,27] (Fig. 1a)
While the HOXD genes themselves are not affected in these conditions, the physical relationship with the flanking regulatory regions are modified, suggesting a potential impact of chromosomal rearrangements upon the long-range regulation of these genes during early limb development[2,11,28]
Summary
Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. 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 These results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31. 1234567890():,; Several human families displaying shortened and bent forearm bones have been reported with large chromosomal rearrangements in the q31 band of chromosome 2, a region containing the HOXD gene cluster[1,2,3,4] They are correlated, the potential involvement of HOX genes in causing these limb dysmorphias (mesomelic dysplasias (MDs)) has never been confirmed, despite various studies in mice indicating that some. This hypothesis was supported by the dominant nature of these malformations in both the human conditions[17] and the mouse Ulnaless mutant[12], the latter being mostly homozygous lethal[14,15]
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