Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes

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.

Truncating variants of the sterol recognition region of SHH cause hypertelorism phenotype rather than hypotelorism‐holoprosencephaly

“…Conditional knockout of Kif3a, resulting in expansion of the Hedgehog responsiveness of the face, has been shown to lead to hypertelorism (Brugmann et al, 2010). In view of such mice experiments, gain‐of‐function mutation in human SHH would lead to excessive expansion of the facial midline or the hypertelorism phenotype (Abramyan, 2019; Dworkin et al, 2016; Niida et al, 2021).…”

Case Report: Prenatal Diagnosis of Postaxial Polydactyly With Bi-Allelic Variants in Smoothened (SMO)

“…Freed of PTCH1-mediated suppression, SMO relieves the sequestration by SUFU and phosphorylation from PKA, CK1, and GSK3β, thus stabilizing the GLI proteins in their full-length transcriptional activator form. The activated GLI (GLIa) translocates into the nucleus and promotes the transcription of SHH target genes ( Figure 1B ) ( Briscoe and Thérond, 2013 ; Niida et al, 2021 ; Sigafoos et al, 2021 ). Here, we observed that the SHH signaling pathway is a highly regulated cascade of extracellular ligands, receptor proteins, cytoplasmic signaling molecules, transcription factors, coregulators, and target genes.…”