Analysis of Mutation Site Structure Prediction and Family Characteristics of Maturity-Onset Diabetes of the Young (MODY) with Ketosis: Caused by HNF4α Gene Mutation.

BACKGROUND: This article aims to examine the clinical and familial characteristics of HNF4α-MODY pa-tients who presented with diabetic ketoacidosis (DKA) or diabetic ketosis (DK). Furthermore, it seeks to explore potential pathogenic mechanisms of the HNF4α mutation and to enhance understanding of ketosis susceptibility in this population. METHODS: We collected detailed medical histories and family histories of two diabetes patients. Whole-exome high-throughput sequencing was performed to identify potential genetic muta-tions. The pathogenicity of the mutations was predicted with PolyPhen-2 and Mutation Taster software. PyMOL software was utilized to analyze the impact of the mutations on the protein structure of HNF4α. RESULTS: Both probands exhibited a decline in pancreatic islet function following disease onset, leading to ineffective sulfonylurea treatment and the development of DKA or DK. Whole-exome se-quencing revealed distinct heterozygous HNF4α mutations in each family. Proband 1, along with her father and elder daughter, carry the c.1331C>T (p. P444L) mutation. Proband 2 and her father harbored the c.929G>C (p. G310A) mutation. Protein structure predictions indi-cates that the c.1331C>T (p. P444L) mutation induces structural changes in the HNF4α pro-tein. Additionally, the c.929G>C (p. G310A) mutation is identified to disrupt hydrogen bonding interactions between the amino acid at position 310 and its surrounding residues. CONCLUSION: The G310A variant likely disrupts homodimer stability, impairing islet function, similar to neighboring pathogenic mutations. On the other hand, the P444L variant is considered likely pathogenic, with its variable expressivity within the family being characteristic of MODY. This study demonstrates that some HNF4α-MODY patients may present with DKA or DK, highlighting the condition's clinical heterogeneity.