We previously reported that
genotype-phenotype correlations in 12 missense variants causing severe insulin
resistance, located in the second and third fibronectin type III (FnIII)
domains of the insulin receptor (INSR), containing the α-β cleavage and part of
insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of
IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently
reported crystal structures of IGF1R. A structural bioinformatics analysis of five
previously reported disease-associated heterozygous missense variants and a
likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core
formation and stability
of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would
not affect the
folding of the domains. A functional analysis of these variants in
CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated
variants, but not in those expressing the wild-type form or the likely benign
variant. These results demonstrated genotype-phenotype
correlations in the FnIII domain variants
of <i>IGF1R</i>, which are presumably
consistent with<i> </i>those of <i>INSR</i> and would help in the early
diagnosis of patients with disease-associated <i>IGF1R</i> variants.
Genotype-Structure-Phenotype Correlations in Disease-Associated IGF1R Variants and Similarities to Those in INSR Variants
