Heterozygous ABCC8 mutations are a cause of MODY

Abstract

Aims/hypothesis The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K ATP ) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. Methods We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m 2 , no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. Results ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. Conclusions/interpretation ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.

Clinical and molecular genetic characteristics of MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing

“…Активирующие же гомо-или гетерозиготные, а также компаунд-гетерозиготные мутации (в дан-ном случае мутантный ген может содержать как ак-тивирующую, так и инактивирующую аллели [24]) являются причиной неонатального СД. Клиниче-ски MODY12 сопоставим с MODY1 и 3; пациенты чувствительны к препаратам сульфонилмочевины [25]. Наш пациент на момент молекулярно-генети-ческого исследования получал терапию метформи-ном, в связи с чем ему была рекомендована госпи-тализация для решения вопроса о модификации терапии.…”

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

“…Mutations in ABCC8 have been previously identified in individuals diagnosed with MODY [122,123]. Other groups have reported that individuals with congenital hyperinsulinemia due to inactivating ABCC8 mutations eventually developed early-and adult-onset diabetes [124,125].…”

Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations

“…More common forms such as GCK, HNF1A, and HNF4A comprise the majority of MODY cases [1][2][3][4][5][6][7][8][9]. Genetic testing for MODY has become a challenge, especially for rarer subtypes and for the completeness of mutation screening using traditional methods, either Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA) [10].…”