Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus

• Published in: Diabetes/metabolism research and reviews Vol. 16; no. 5; pp. 370 - 377
• Main Authors: Celi, Francesco S., Negri, Carlo, Tanner, Keith, Raben, Nina, De Pablo, Flora, Rovira, Adela, Pallardo, Luis F., Martin-Vaquero, Pilar, Stern, Michael P., Mitchell, Braxton D., Shuldiner, Alan R.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2000; Wiley
• Subjects: Adult; Aged; Amino Acid Substitution; Biological and medical sciences; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Family; Female; Genetic Variation; genetics; Genotype; Humans; Insulin Receptor Substrate Proteins; insulin resistance; Male; Medical sciences; Metabolic diseases; Mexican Americans - genetics; Middle Aged; noninsulin dependent diabetes mellitus; Obesity; Pedigree; Phosphoproteins - genetics; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; single-stranded conformational polymorphisms; Texas; Texas; Endocrinopathy; Human; Obesity; Enzyme; Pathogenesis; Transferases; Nutrition disorder; Non insulin dependent diabetes; Insulin; Target tissue resistance; Mutation; Molecular biology; Protein-tyrosine kinase; Nutritional status; Hormonal receptor
• ISSN: 1520-7552; 1520-7560
• DOI: 10.1002/1520-7560(2000)9999:9999<::AID-DMRR129>3.0.CO;2-B

Background Insulin receptor substrate‐1 (IRS‐1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays an important role in insulin signaling. Mutations in the IRS‐1 gene are associated in some populations with obesity and Type 2 diabetes. Methods To determine whether variation in the IRS‐1 gene contributes to genetic susceptibility to insulin resistance and Type 2 diabetes in Mexican Americans, the entire coding region of the IRS‐1 gene was screened for variation in 31 unrelated subjects with Type 2 diabetes using single‐stranded conformational polymorphism analysis (SSCP) and dideoxy sequence analysis. Variants encoding amino acid substitutions were genotyped in 27 unrelated nondiabetic Mexican Americans and in all family members of subjects containing these variants, and association analyses were performed. To trace the ancestral origins of the variants, Iberian Caucasians and Pima Indians were also genotyped. Results Eight single base changes were found: four silent polymorphisms and four missense mutations (Ala94Thr, Ala512Pro, Ser892Gly and Gly971Arg). Allele frequencies were 0.009, 0.017, 0.017 and 0.043, respectively. There were no significant associations of any of these variants with diabetes, glucose or insulin levels during an oral glucose tolerance test, or with body mass index (BMI) in Mexican American families except for a modest association between the Ala94Thr variant and decreased BMI (30.4 kg/m2 vs 24.0 kg/m2; p=0.035). None of these four missense mutations were detected in Pima Indians. In Iberian Caucasians, neither Ala94Thr nor Ser892Gly were detected, and Ala512Pro was detected in only 0/60 diabetic patients and 1/60 nondiabetic controls. Gly971Arg was relatively more common in Iberian Caucasians with 12/58 diabetic patients and 7/60 nondiabetic controls being heterozygous for this variant (p=0.21 for comparison between diabetic and nondiabetic subjects). Conclusions Ala94Thr, Ala512Pro and Ser892Gly mutation are rare in the populations studied. Gly971Arg, is more common in Mexican Americans and Caucasians, but is not a major contributor to genetic susceptibility to Type 2 diabetes. Copyright © 2000 John Wiley & Sons, Ltd.