Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity‐onset diabetes of the young type‐2 (MODY2, also known as GCK‐MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4–8.3 mmol L−1, and rarely develops complications from diabetes. The treatment of MODY2 prefers a manageable diet rather than the use of insulin. Previous studies have identified GCK mutations only by online software prediction or enzyme kinetic analysis and thermolability assays which are complicated to be conducted. In this study, six mutations in the GCK gene, including four novel mutations and two mutations that are previously reported, are identified. All the six locations are highly conserved according to the sequencing alignment. Moreover, missense mutations are strongly predicted to be pathogenic using online programs. Functional studies show that mutations in GCK mutation do not affect insulin secretion but affect glycogen synthesis. These findings demonstrate that GCK mutations decrease glycogen synthesis, which leads to hyperglycemia in MODY2. Meanwhile, this study provides a new perspective and methods for identifying pathogenic mutations in GCK.

Background. Kallmann syndrome (KS) is a rare genetic disease characterized by the reproductive system and olfactory dysplasia due to the defective migration of gonadotropin-releasing hormone (GnRH) neurons. However, this disorder is clinically heterogeneous and the genotype-phenotype relationship has not been determined. Objective. The present study aimed to identify the variant causing KS in a Chinese family and evaluate the functional consequences and phenotypes associated with the novel variant. Methods. A Chinese family with KS was screened for pathogenic variants by whole-exome sequencing (WES). Bioinformatic analysis was performed to predict the consequences of the identified variant. The expression of the mutant protein was examined in vitro. Results. A novel heterozygous variant (NM_006080.2 : c.814G > T) in SEMA3A was identified in the patient and his father, which caused the substitution of aspartic acid with tyrosine in codon 272. It was predicted to result in pathogenic significance with a high damaging score and seriously affect protein structure by bioinformatic analysis. In vitro experiments revealed this variant could significantly decrease the expression of SEMA3A. Furthermore, it may cause the disease by failing to induce the phosphorylation of focal adhesion kinase (FAK) in GnRH neurons. Conclusion. Identification and functional characterization of this novel variant in the SEMA3A gene in a Chinese family with Kallmann syndrome extend the genetic variant spectrum of SEMA3A and provide more data about the heterogeneity of KS, which may provide further insights into the diagnosis of KS and help patients get additional data in genetic counseling and timely treatment.