Abstract
Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. In this review, we summarize the molecular mechanisms and role in embryonic morphogenesis of the SHH pathway, then classify the phenotype of each malformation syndrome associated with mutations of major molecules in the pathway. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb. The symptoms of each syndrome can be explained by the GLIA/R balance model.
Highlights
Hedgehog (HH) is a key morphogen involved in patterning during embryonic development; the HH pathway regulates pattern formation in various organs
sonic hedgehog (SHH) is expressed in the zone of polarizing activity (ZPA) of the limb bud [3,7,9,10], and in those of the notochord and floor plate in the neural tube [11,12]
It does not matter whether its function is the same as or vice versa of the function that a normal gene product gives to the SHH pathway
Summary
Hedgehog (HH) is a key morphogen involved in patterning during embryonic development; the HH pathway regulates pattern formation in various organs. Three mammalian homologs—sonic hedgehog (SHH), Indian hedgehog (IHH) and desert hedgehog (DHH)—were discovered, and an evolutionarily conserved role for these molecules in developmental patterning established [2,3,4,5,6,7]. Much research on the SHH pathway has been done, and due to the general cross-species conservation of function, studies using animal models were instrumental in understanding its basic functions. The phenotypes of hereditary malformation syndromes in humans do not always recapitulate those of. It is necessary to characterize and classify the human phenotypes caused by mutations SHH pathway genes, to better understand the functions of these genes in human development. We classify the phenotypes of human malformation syndromes due to mutations in the major constituent genes of the SHH pathway
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