INSR – Donohue syndrome

Donohue syndrome is a rare, autosomal recessive disorder caused by biallelic loss-of-function mutations in the insulin receptor gene INSR. Affected individuals present with severe intrauterine growth retardation, elfin facies, hypertrichosis, and extreme insulin resistance leading to early mortality. The clinical phenotype overlaps with Rabson-Mendenhall syndrome but represents the most severe end of the spectrum of INSR-related insulin resistance syndromes.

Genetic evidence for the INSR–Donohue syndrome association is strong. Over 30 unrelated probands have been reported carrying homozygous or compound heterozygous INSR variants—nonsense, frameshift, missense, splice-site, and exon-deletion alleles—all following autosomal recessive inheritance (PMID:2300553, PMID:1315125). Consanguineous families demonstrate complete segregation of INSR mutations with the phenotype, including five affected siblings homozygous for p.Ile146Met in one pedigree (PMID:7815442).

Case series encompass both private and recurrent alleles. The first described nonsense variant, c.2770C>T (p.Arg924Ter), reduces receptor mRNA to <10% of normal in patient fibroblasts (PMID:2300553). More than 15 missense substitutions (e.g., p.His236Arg, p.Trp439Ser) impair receptor processing, cell-surface expression, or kinase activity. Frameshift and splice-site lesions (e.g., exon 3 deletion) have also been documented, with founder deletions reported in Middle Eastern populations (PMID:19774849).

Functional studies have elucidated the mechanism of pathogenicity. Mutant receptors commonly fail to undergo proteolytic α/β cleavage, leading to retention of a 210-kDa proreceptor and impaired insulin binding and autophosphorylation (PMID:1657953, PMID:8188715). Kinase-domain substitutions selectively abrogate insulin-stimulated downstream signaling without affecting ligand binding, while α-subunit variants interfere with disulfide-linked dimerization and membrane trafficking.

In vivo and rescue experiments support clinical relevance. Recombinant human IGF-1 infusion in patients and mouse knock-in models only partially ameliorates hyperglycemia, underscoring a primary receptor defect (PMID:7534902). Continuous subcutaneous rhIGF-1 via insulin pump has transiently improved metabolic control but does not restore normal growth or survival beyond early infancy.

Together, genetic and experimental data fulfill ClinGen criteria for a strong gene–disease association. INSR mutations result in receptor haploinsufficiency or dominant-negative effects, converging on impaired insulin signaling and extreme insulin resistance. This body of evidence supports diagnostic sequencing of INSR in neonates with severe insulin resistance and informs therapeutic trials of IGF-1.

Key take-home: Biallelic INSR variants cause definitive Donohue syndrome with consistent genotype–phenotype correlation and functional loss-of-function, guiding genetic diagnosis and management strategies.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1990 • A nonsense mutation causing decreased levels of insulin receptor mRNA: detection by a simplified technique for direct sequencing of genomic DNA amplified by the polymerase chain reaction. PMID:2300553
• The Journal of biological chemistry • 1991 • Substitution of arginine for histidine at position 209 in the alpha-subunit of the human insulin receptor. A mutation that impairs receptor dimerization and transport of receptors to the cell surface. PMID:1657953
• American journal of human genetics • 1992 • Reduced mRNA and a nonsense mutation in the insulin-receptor gene produce heritable severe insulin resistance. PMID:1315125

Evidence Based Scoring (AI generated)