Human HOX gene disorders

Abstract

The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

What limits the morphological disparity of clades?

“…Ichthyosaurs furnish the best-known exception: opthalmosaurians added digits anterior to digit one and posterior to digit five [196], whereas non-opthalmosaurians may have achieved polydactyly by interdigital or postaxial phalangeal bifurcation [197]. In most amniote groups, however, polydactyly is associated with a range of deleterious pleiotroipic effects [198][199][200], because limb development coincides with the phylotypic stage. Variation in this particular set of characters appears to be effectively locked down, therefore.…”

Cellular and molecular insights into Hox protein action

“…Importantly, variation in Hox gene number, expression pattern and protein activity has played a major role in the evolution of the metazoan body plan (Gellon and McGinnis, 1998). Hox genes have also been associated with a number of human diseases (Quinonez and Innis, 2014), highlighting the fact that Hox proteins are key factors in development, evolution and physiopathological processes.…”

Increased prevalence of abnormal vertebral patterning in fetuses and neonates with trisomy 21

“…These 39 genes are an evolutionary conserved family of genes that play a key role in the development of anteroposterior axis, but also in other physiologic and pathologic processes, such as oncogenesis [38,39]. Several experiments on chicks and mice have shown that Hox-gene mutations can lead to homeotic transformations [40].…”