INSR – Type A Insulin Resistance Syndrome

Type A insulin resistance syndrome is a rare autosomal dominant disorder caused by heterozygous or, rarely, homozygous mutations in the insulin receptor gene, INSR. Clinically, affected individuals present with severe hyperinsulinemia, insulin resistance, acanthosis nigricans and often hyperandrogenism in females. Genetic testing of INSR is critical for accurate diagnosis, guiding management, and family screening in patients with unexplained severe insulin resistance.

1. Clinical Validity

Based on over 30 probands from more than 20 independent families and segregation in ≈19 affected relatives ([PMID:9112018]; [PMID:31771632]), the INSR–type A insulin resistance syndrome association meets the Strong ClinGen category. This classification reflects multiple unrelated cases, clear autosomal dominant transmission and concordant experimental data.

2. Genetic Evidence

Inheritance is autosomal dominant, with most patients carrying heterozygous missense mutations in the tyrosine kinase domain. Segregation analyses have identified the same variant in up to 3 additional affected relatives per pedigree. Case reports describe at least 1 homozygous proband causing Donohue-like features ([PMID:9112018]) and 10 heterozygous patients from 5 Saudi families harboring the c.433C>T (p.Arg145Cys) founder mutation ([PMID:22017372]).

3. Variant Spectrum

Pathogenic variants are predominantly missense changes clustering in the kinase and ligand-binding domains. Recurrent/founder alleles include c.433C>T (p.Arg145Cys) in Saudi cohorts. Other documented variants span exon 19 (c.3601C>T (p.Arg1201Trp)), exon 17 (c.3472C>T (p.Arg1158Trp)) and exon 20 (c.3614C>T (p.Pro1205Leu)).

4. Mechanism & Functional Evidence

Most INSR mutations impair tyrosine kinase activity either by misfolding or dominant-negative effects. In vitro studies of p.Arg145Cys demonstrated an 83% reduction in insulin binding and markedly decreased autophosphorylation in CHO cells, consistent with impaired downstream signaling ([PMID:22017372]). Kinase-defective alleles also show reduced glucose transport and glycogen synthesis in patient fibroblasts and rescue by IGF-I stimulation in lymphocytes ([PMID:9112018]).

5. Conflict & Integration

No conflicting studies refute the INSR–type A insulin resistance link. The combined genetic and functional evidence coherently supports a dominant-negative mechanism underlying severe insulin resistance. While additional complex alleles have been described, they reinforce the core pathogenic model rather than dispute it.

Key Take-home: Genetic testing for INSR mutations is essential for diagnosing type A insulin resistance syndrome, enabling precise management and family screening.

References

• Diabetologia • 1997 • A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism PMID:9112018
• Clinical Endocrinology • 2012 • Molecular characterization of a novel p.R118C mutation in the insulin receptor gene from patients with severe insulin resistance PMID:22017372
• Gynecological Endocrinology • 2020 • Arg1201Gln mutation of insulin receptor impairs tyrosine kinase activity and causes insulin resistance: a case report PMID:31899992
• Journal of Medical Case Reports • 2019 • Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report PMID:31771632

Evidence Based Scoring (AI generated)