Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants.
Diabetes
; 70(8): 1874-1884, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-34074726
ABSTRACT
We previously reported 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-ß 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-ß 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 IGF1R, which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estatura
/
Receptor de Insulina
/
Antígenos CD
/
Receptor IGF Tipo 1
/
Transtornos do Crescimento
Tipo de estudo:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Screening_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão