ESPE Abstracts

Background: Over 800 different mutations in GCK gene have been reported in the Human Gene Mutation Database, the vast majority of which result in monogenic diabetes (Maturity Onset Diabetes of the Young, MODY type 2). The missense mutation p.Leu122Val is listed in that database as "disease-causing". However, the National Center for Biotechnology Information ClinVar database (Variation ID 585919) reports that this mutation is of "uncertain significance". Both databases refer to an Italian pediatric patient reported by Massa et al in 2001.

Objective: To report a pedigree of 3 patients affected with GCK mutation c.364C>G (p.Leu122Val) to support the pathogenicity of this mutation.

Cases: Proband (case 1) is an African-American female who was diagnosed with diabetes at 3 years of age. She was initially treated for type 1 diabetes with basal/bolus insulin. Her diabetes autoantibodies were negative and she required low doses of insulin. Her insulin was discontinued upon discovery of a mutation in the GCK gene suggestive of MODY type 2. Her HgbA1c has since ranged from 6.8 - 7.2% without insulin therapy.

Case 2 is the younger half-sister of case 1. She was initially seen at 3 years of age for an elevated fasting glucose level of 118 mg/dl (6.55 mmol/L) and HgbA1c of 6.4%.

Case 3 is the mother of case 1 and 2. She had a history of insulin-requiring gestational diabetes with her second pregnancy, and received metformin therapy for 8 months post-partum. At a clinic visit with her daughters, she was found to have a fasting glucose of 129 mg/dl (7.16 mmol/L) and HgbA1c of 6.3%.

Results: Genetic analysis in the three cases revealed GCK mutation c.364C>G (p.Leu122Val). The maternal grandmother of cases 1 and 2 also had genetic testing performed that was negative for the mutation.

The potential pathogenic role of this mutation was evaluated in silico by Polyphen2, SIFT, and Mutation Taster. The mutation was considered to be "probably damaging", "damaging", and "disease-causing" respectively by those bioinformatics tools.

Conclusions: To our knowledge, the GCK mutation c.364C>G (p.Leu122Val) has only been reported in a pediatric patient in Italy and was without a phenotypic description. The description of these three family members over two generations strengthens the supposition that this mutation is indeed disease-causing and of clinical significance.

References: Massa O, Meschi F, Cuesta-Munoz A, et al 2001. Diabetologia 44:898–905.