Four Mutant Alleles of the Insulin Receptor Gene Associated with Genetic Syndromes of Extreme Insulin Resistance

• Published in: Biochemical and biophysical research communications 1997-08, Vol.237 (3), p.516-520
• Main Authors: Kadowaki, Hiroko, Takahashi, Yoshihiko, Ando, Akifumi, Momomura, Kaoru, Kaburagi, Yasushi, Quin, John D., Maccuish, Angus C., Koda, Naoya, Fukushima, Yoshimitsu, Taylor, Simeon I., Akanuma, Yasuo, Yazaki, Yoshio, Kadowaki, Takashi
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Base Sequence; Cell Line; Female; Growth Disorders - genetics; Heterozygote; Humans; Insulin Resistance - genetics; Introns; Lymphocytes; Male; Mutagenesis, Site-Directed; Mutation; Point Mutation; Receptor, Insulin - biosynthesis; Receptor, Insulin - chemistry; Receptor, Insulin - genetics; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Sequence Deletion; Syndrome; Transfection
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1997.7181

We identified four novel mutant alleles of the insulin receptor gene in three patients with genetic syndromes associated with insulin resistance. Two mutant alleles of the insulin receptor gene were identified in a patient with the Rabson-Mendenhall syndrome who was a compound heterozygote for a mutation at the 3′-splice acceptor site of intron 4 (AG→GG), the first mutation causing an aberrant splicing at this locus, and a deletion of eight base pairs in exon 12. The second patient with leprechaunism was also a compound heterozygote for a deletion of one base pair in exon 19 and a mutation, Thr910→Met, which causes impaired receptor processing. Interestingly, the third patient with type A syndrome was a simple heterozygote for the identical one base pair deletion. The fact that the same one base pair deletion links to type A in a simple heterozygote and to leprechaunism in a compound heterozygote appears consistent with the hypothesis that the severity of mutations will determine the phenotype.