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

Am J Hum Genet. 2020 Jun 4;106(6):779-792. doi: 10.1016/j.ajhg.2020.04.010. Epub 2020 May 14.


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 bi-allelic 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.

Keywords: SMO; ciliopathies; developmental anomalies; hedgehog signaling; human genetics; primary cilium; smoothened.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Base Sequence
  • Child
  • Child, Preschool
  • Cilia / physiology
  • Developmental Disabilities / genetics*
  • Female
  • Hedgehog Proteins / metabolism*
  • Humans
  • Infant
  • Male
  • Models, Molecular
  • Neoplasms / genetics
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Pedigree
  • Signal Transduction*
  • Smoothened Receptor / genetics*
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3


  • GLI2 protein, human
  • GLI3 protein, human
  • Hedgehog Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SMO protein, human
  • Smoothened Receptor
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3