Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations

RET tyrosine kinase is essential for various developmental processes, and loss-of-function ret missense mutations cause Hirschsprung's disease (HSCR). Structural studies identified residues that constitute a crucial folding bottleneck relevant to the maturation of RET in the endoplasmic reticulum, and the maturation efficiency of ret mutants correlates well with their severity in patients with HSCR disease.