Domain structure of human SMO and variant annotation
The SMO transcript encodes a typical domain structure of a GPCR-like signal transducer (Fig.1A, 1B) that traffics from intracellular pools to the plasma membrane and ultimately through the cilium following ligand stimulation. A key feature of SMO is its heptahelical transmembrane domain, that is the site of natural and synthetic agonist and antagonist binding as well as activating mutations in human cancers. The seven missense variants detected among HPE probands are described in Table 1 and their positions are annotated in Fig.1B. The primary amino acid comparison data indicates that the mutant residues p.R113, p.R199, p.V404, p.R772 are largely evolutionarily conserved (Fig.1C). However, the potential consequences of the variations are difficult to predict.