Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Abstract Heterozygous coding mutations in the INS gene that encodes preproinsulinwere recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-celldeath through endoplasmic reticulum stress and apoptosis. We now report 10 different recessiveINS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessivemutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylationsignal. A subset of recessivemutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-celldefect, patients with recessiveINS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetesas a result of two contrasting pathogenic mechanisms. Moreover, the recessivelyinherited mutations provide a genetic demonstration of the essential role of multiple sequenceelements that regulate the biosynthesis of insulin in man.