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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.

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