INS – Permanent Neonatal Diabetes Mellitus

Permanent neonatal diabetes mellitus (PNDM) is a rare monogenic disorder marked by insulin deficiency and persistent hyperglycemia within the first six months of life. The insulin gene (INS) encodes proinsulin, which undergoes folding, processing, and secretion by pancreatic β-cells. Pathogenic variants in INS disrupt these processes, leading to PNDM (MONDO:0100164). Early genetic diagnosis guides treatment, optimizes long-term outcomes, and informs family planning.

Heterozygous de novo and inherited missense mutations in INS have been identified in multiple unrelated PNDM probands. Seven patients from four families carried heterozygous coding variants in a U.S. cohort diagnosed before 1 year (7 probands) (PMID:18662362), and ten unrelated probands harbored seven distinct heterozygous missense proinsulin mutations (10 probands) (PMID:18451997). Additional homozygous variants include a novel promotor mutation c.-331C>G in two siblings with PNDM and childhood-onset autoantibody-negative diabetes (PMID:35140529) and a c.1T>C initiation codon variant in a Chinese patient followed over 10 years (PMID:36686471).

The variant spectrum spans missense substitutions affecting disulfide bonds (e.g., c.265C>T (p.Arg89Cys)), promoter mutations, and initiation codon loss. Recurrent de novo hotspots include mutations at B-chain positions critical for folding. There is no clear founder allele; most coding mutations arise independently across ethnicities. Phenotypically, affected neonates present with low birth weight and small for gestational age (HP:0001518), ketoacidosis (HP:0001993), and lifelong insulin dependence.

Functional studies demonstrate that INS missense mutants impair proinsulin oxidative folding, induce endoplasmic reticulum stress, and exert dominant-negative effects on co-expressed wild-type proinsulin. Expression of p.Arg89Cys in HEK293 cells led to misfolding, increased GRP78 and XBP1 splicing, and β-cell apoptosis (PMID:18451997). A zebrafish C43G transgenic model confirmed ER retention without overt hyperglycemia (PMID:24843647). A homozygous promoter c.-331C>G mutation abrogates KLF11 binding and recapitulates insulin deficiency in Klf11–/– mice (PMID:21592955). Inefficient preproinsulin translocation by nonsense variants further underscores the importance of signal peptide integrity (PMID:35069438).

No studies have refuted the INS–PNDM association. The cumulative genetic and functional evidence meets ClinGen Definitive criteria, with consistent findings across >20 probands, including segregation data and concordant experimental models. Genetic testing for INS variants is critical for early diagnosis, appropriate insulin therapy, and genetic counseling.

Key Take-home: INS mutations cause PNDM via disrupted proinsulin folding/secretion; early genetic diagnosis and tailored insulin management yield favorable long-term outcomes.

References

• Frontiers in endocrinology • 2022 • Case report: A 10-year prognosis of neonatal diabetes caused by a novel INS gene mutation. PMID:36686471
• International medical case reports journal • 2022 • Homozygous Insulin Promotor Gene Mutation Causing Permanent Neonatal Diabetes Mellitus and Childhood Onset Autoantibody Negative Diabetes in the Same Family. PMID:35140529
• The Journal of clinical investigation • 2008 • Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. PMID:18451997
• Pediatric diabetes • 2008 • Diagnosis and treatment of neonatal diabetes: a United States experience. PMID:18662362
• Journal of diabetes investigation • 2013 • Transgenic zebrafish model of the C43G human insulin gene mutation. PMID:24843647
• The Journal of biological chemistry • 2011 • Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. PMID:21592955
• Frontiers in endocrinology • 2021 • A Novel Nonsense INS Mutation Causes Inefficient Preproinsulin Translocation Into the Endoplasmic Reticulum. PMID:35069438

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