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INS – Transient Neonatal Diabetes Mellitus

Transient neonatal diabetes mellitus (TNDM) is characterized by onset of hyperglycemia within the first six months of life with remission typically by 18 months. A homozygous INS promoter variant, c.-331C>G, was identified in a patient with TNDM who experienced spontaneous remission by 18 months of age (PMID:26463504). No additional family members were affected, supporting a recessive mechanism.

Functional assays demonstrate that the c.-331C>G change disrupts a Kruppel-like factor 11 (KLF11) binding site in the INS promoter, leading to impaired transcriptional activation in vitro and reduced insulin expression in Klf11(-/-) mice (PMID:21592955). These data concordantly indicate a loss-of-function mechanism for this promoter mutation.

References

  • American journal of medical genetics. Part A • 2016 • Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates. PMID:26463504
  • 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

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single unrelated proband with a homozygous c.-331C>G INS promoter variant showing transient neonatal diabetes (<18 months) ([PMID:26463504])

Genetic Evidence

Limited

One homozygous INS variant in a single TNDM case ([PMID:26463504])

Functional Evidence

Moderate

c.-331C>G disrupts KLF11 binding in reporter assays and Klf11(-/-) mice phenocopy reduced insulin production ([PMID:21592955])