De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic...

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Hepatology

Background:

• Permanent neonatal diabetes mellitus (PNDM) results from impaired pancreatic beta-cell function or reduced cell numbers.
• Understanding the genetic underpinnings of PNDM offers insights into fundamental beta-cell biology.

Purpose of the Study:

• To identify causative de novo variants in patients with PNDM through trio genome sequencing.
• To investigate the role of novel genetic variants in PNDM and associated conditions.

Main Methods:

• Trio genome sequencing was conducted on 44 PNDM patients and their parents.
• Replication studies involved 188 additional patients with early-onset diabetes.
• Analysis focused on identifying de novo mutations in candidate genes, particularly EIF2B1.

Main Results:

• Novel de novo missense variants in the EIF2B1 gene were identified in multiple PNDM patients.
• These mutations were associated with both diabetes and childhood hepatitis-like episodes.
• Mutations clustered on a critical protein surface, suggesting a mechanism of impaired eIF2B complex function.

Conclusions:

• De novo mutations in EIF2B1 represent a newly identified cause of permanent diabetes and liver dysfunction.
• These findings underscore the importance of cell stress regulation pathways for beta-cell survival and function.
• EIF2B1 plays a crucial role in sensing cellular stress and maintaining beta-cell homeostasis.