The INS gene encodes proinsulin, the precursor to the insulin hormone. Proinsulin is post-transcriptionally cleaved into the A and B chain peptides by the removal of the C (or ‘connecting’) chain peptide. These two chains are then linked by 2 disulfide bonds to form the mature insulin protein. Insulin is essential for decreasing glucose levels in the body. It does this by increasing cell permeability to monosaccharides, amino acids and fatty acids as well as accelerating glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
The gene has been associated with Diabetes Mellitus, Insulin-Dependent, 2 (IDDM2), a Type 1 diabetes disorder. It is also implicated in Permanent Neonatal Diabetes Mellitus (PNDM), a disorder characterized by an infantile onset of hyperglycemia. The gene is also responsible for Hyperproinsulinemia and Maturity-Onset Diabetes of the Young, Type 10 (MODY10).
The INS gene is located on the short arm of chromosome 11 and spans a length of 1.5 kb of DNA. Its coding sequence is contained within 3 exons and it encodes an 11.9 kDa protein product made up of 110 amino acids. An additional isoform consisting of 200 amino acids exists due to alternative splicing. The gene is overexpressed in the Islet of Langerhans cells of the pancreas. Most mutations detected in INS associated with Type 1 diabetes, PNDM, Hyperproinsulinemia or MODY10 are missense variants. Around 10 mutations in the gene have been implicated in PNDM
Deeb et al. (2016) studied Neonatal Diabetes Mellitus (NDM) patients and characterized their genetic and clinical features. The authors found 25 cases of NDM in Abu Dhabi between the years 1985-2013, giving an incidence rate of 1:29,241 live births. Of these, 23 were Permanent Neonatal Diabetes Mellitus (PNDM) cases and 2 patients had Transient Neonatal Diabetes Mellitus (TNDM). Genetic analysis of these patients revealed the INS c.-331C>G mutation in 9 members of two unrelated families. However, the age of onset, duration of disease and insulin requirement varied even between siblings. In one family with 5 affected members, 2 were diagnosed at 6 weeks, one at 13 years, one at 18 years and one in the first hour of life. In the second family, all four affected siblings presented with hyperglycemia at 2 days of age. Of these, one sibling underwent remission, no longer requiring insulin. She was diagnosed with TNDM. Another sibling succumbed to sepsis at two weeks of age.
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