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Novel Pathogenic De Novo INS p.T97P Variant Presenting With Severe Neonatal DKA.

ABSTRACT: Pathogenic INS gene mutations are causative for mutant INS-gene-induced diabetes of youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response.

SUBMITTER: Lal RA 

PROVIDER: S-EPMC9017997 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Novel Pathogenic De Novo INS p.T97P Variant Presenting With Severe Neonatal DKA.

Lal Rayhan A RA   Moeller Hannah P HP   Thomson Ella A EA   Horton Timothy M TM   Lee Sooyeon S   Freeman Raquel R   Prahalad Priya P   Poon Ada S Y ASY   Annes Justin P JP  

Endocrinology 20220201 2

Pathogenic INS gene mutations are causative for mutant INS-gene-induced diabetes of youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and lu  ...[more]

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