Novel Pathogenic De Novo INS p.T97P Variant Presenting With Severe Neonatal DKA-Reference-Cited by-同舟云学术

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

Published:2021-12-09 Issue:2 Volume:163 Page:
ISSN:0013-7227
Container-title:Endocrinology
language:en
Short-container-title:

Author:

Lal Rayhan A¹²³^ORCID,Moeller Hannah P³⁴^ORCID,Thomson Ella A⁵^ORCID,Horton Timothy M¹⁶^ORCID,Lee Sooyeon¹^ORCID,Freeman Raquel⁷,Prahalad Priya²³^ORCID,Poon Ada S Y⁵^ORCID,Annes Justin P¹³^ORCID

Affiliation:

1. Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA

2. Division of Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA, USA

3. Stanford Diabetes Research Center, Stanford, CA, USA

4. Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA

5. Department of Electrical Engineering, Stanford University, Stanford, CA, USA

6. Department of Chemistry, Stanford University, Stanford, CA, USA

7. Department of Bioengineering, Stanford University, Stanford, CA, USA

Abstract

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.

Funder

NIH NIDDK

Stanford Diabetes Research Center

Stanford Maternal and Child Health Research Institute

Stanford Molecular Pharmacology Training

Stanford Bio-X Interdisciplinary Initiatives Seed

Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program

Bio-X Interdisciplinary Graduate Fellowship

Endocrinology Training

Publisher

The Endocrine Society

Subject