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Endocrine Abstracts (2014) 35 P371 | DOI: 10.1530/endoabs.35.P371

1Centro Hospitalar do Porto, Porto, Portugal; 2CGC Genetics, Porto, Portugal.

Introduction: Glucokinase-MODY (Maturity onset diabetes of the young) results from heterozygous mutations in the GCK gene, impairing its enzymatic activity. GCK acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. We describe two cases of MODY due to a GCK gene mutation not described until now.

Clinical Case: A 63-year-old male is followed in our hospital for 30 years due to diabetes mellitus (DM). He was diagnosed in his twenties and his family history was strongly positive for diabetes (maternal grandmother, mother and two brothers). He always had a good metabolic control (HbA1c 6–6.8%) under oral anti-diabetic medication (currently under metformin and sitagliptin). Nowadays the only complication is an increased albuminuria (92.5 mg/g creatinine) under irbesartan 300 mg/day. His son is 25 years-old and was diagnosed with diabetes at age 4, by routine analysis. Type 1 diabetes-specific antibodies were always negative, as were his father’s. He never needed anti-diabetic medication due to good glycemic control (HbA1c 5.3–6.1%), such that he has only been on diet. He has no complications of the disease.

Both clinical presentations were highly suggestive of GCK-MODY, so a sequencing analysis of the GCK gene was done on both patients and a c.1318G>T (p.Glu440X) heterozygous loss-of-function mutation encoded on exon 10 was identified. It introduces a premature stop codon in the synthesis of GCK, impairing its activity and likely being a GCK-MODY causing mutation.

Conclusion: There are more than 600 mutations described over the GCK gene, some of them causing MODY. Only a few have been detected in exon 10. We report a heterozygous mutation in the exon 10 of the GCK gene still not described in the literature, which results in the typical GCK-MODY phenotype, found in two members of different generations of the same family.

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