Novel allele of the insulin receptor substrate-1 bearing two non-conservative amino acid substitutions in a patient with noninsulin-dependent diabetes mellitus

• Published in: Human mutation Vol. 11; no. 5; p. 411
• Main Authors: Mammarella, Sandra, Creati, Beatrice, Esposito, Diana L., Arcuri, Paola, Della Loggia, Fulvio, Capani, Fabio, Mariani-Costantini, Renato, Caramia, Felice Giacomo, Battista, Pasquale, Cama, Alessandro
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 1998; John Wiley & Sons, Inc
• Subjects: IRS-1: Insulin receptor substrate-1 gene; NIDDM: Noninsulin dependent diabetes mellitus OMIM 125853; SSCP: Single strand conformation polymorphism
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU12>3.0.CO;2-#

We analyzed by SSCP the complete IRS‐1 coding sequence in NIDDM patient #25 D. Unique conformers corresponding to a Ser to Tyr substitution at codon 1043 (S1043Y), and to a Cys to Tyr substitution at codon 1095 (C1095Y) were detected in this patient. The results of sequential digestion with restriction enzymes indicated that the novel sequence variants segregate on the same allele. Relatives of patient #25 D were not available for study, to confirm segregation of the novel allele with NIDDM in the family. Several lines of evidence suggest that the non‐conservative amino acid substitutions detected in NIDDM patient #25 D have the potential to affect IRS‐1 functions and could play a pathogenic role in this patient. Both S1043Y and C1095Y occur in a highly conserved sequence from human skeletal muscle, human hepatoma, mouse, and rat IRS‐1. Protein subsequence analysis revealed that the S1043Y substitution abolishes a consensus sequence for glycogen synthase kinase 3 phosphorylation. Furthermore, S1043Y and C1095Y are not common IRS‐1 polymorphisms as they were detected only in 1/136 chromosomes from NIDDM patients (allele frequency in NIDDM patients = 0.007) and in 0/120 chromosomes from control subjects. Hum Mutat 11:411, 1998. © 1998 Wiley‐Liss, Inc.