Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling

Abstract

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report biallelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.

Rare hypomorphic human variation in the heptahelical domain ofSMOcontributes to holoprosencephaly phenotypes

“…Previous report revealed that bi‐allelic variants of SMO induce development anomalies include dysmorphic facial feature and cardiac defect. Variants have several causes on TMD and ICD: several point mutation, around 30 Kb deletion including SMO exon1 or crucial residues mutation (Le et al, 2020). There are not same residues mutation of current report in the report.…”

“…The role of nonclassical GPCR signaling via SMO in human pathologies is less clearly understood (Arensdorf, Marada, & Ogden, 2016; Qi et al, 2019). Le reported that bi‐allelic variants of SMO in human cause a broad spectrum of developmental anomalies: gelastic epilepsy, hypothalamic hamartoma, dysmorphic facial features and postaxial polydactyly and so forth, due to abnormal Hh signaling (Le et al, 2020). However, the heptahelical domain is the frequent target for recurrent activating mutations in cancer and somatic mosaic mutations in malformation syndromes, such as Curry‐Jones (Ayers and Thérond, 2010; Lam et al, 1999; Taipale et al, 2000; Twigg et al, 2016; Xie et al, 1998), while variation within the remaining domains characteristic of the GPCR superfamily are less frequently observed.…”

FBW7 couples structural integrity with functional output of primary cilia

“…Interestingly, bi-allelic loss-of-function variations in SMO or Hedgehog acyl-transferase (HHAT) genes in humans led to many developmental anomalies including microcephaly 56,57 . While it is unknown whether microcephaly in humans caused by inactivating mutations in NDE1 is due to abnormally long cilia and/or reduced Hedgehog activity (GLI2), our data lend support to this idea.…”

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

“…In contrast, the complete absence of SMO or SHH in mouse models resulted in holoprosencephaly because SHH is required for cell migration and axonal guidance in the developing brain. Bi-allelic SMO variations causing the loss of SMO function in humans resulted in variable phenotypes, including hypothalamic hamartomas and microcephaly, shortening of limb bones, narrow chest and heart defects, probably due to defects in HH signalling, which was confirmed in studies of patient fibroblasts [ 113 ].…”