ABCMdb

PMID: 21544516

Russo L, Iafusco D, Brescianini S, Nocerino V, Bizzarri C, Toni S, Cerutti F, Monciotti C, Pesavento R, Iughetti L, Bernardini L, Bonfanti R, Gargantini L, Vanelli M, Aguilar-Bryan L, Stazi MA, Grasso V, Colombo C, Barbetti F
Permanent diabetes during the first year of life: multiple gene screening in 54 patients.
Diabetologia. 2011 Jul;54(7):1693-701. Epub 2011 Mar 10., [PubMed]

Sentences

No. Mutations Sentence Comment

41 ABCC8 p.Val324Met ABCC8 p.Ala355Thr ABCC8 p.Leu213Pro ABCC8 p.Leu213Pro ABCC8 p.Trp688Arg The other patient (group 2) Table 1 Clinical and genetic features of patients with diabetes onset within the first year of life studied in the present investigation Patient T1D autoantibodies tested Age at onset (days) Gene variant Other features SU treatment Group 1 nd-VI/1 ICA, GADA, IA-2A 1 KCNJ11/V59A DEND Yes nd-BR/1 None 2 - Diarrhoea nd-RM/4 IAA, GADA, IA-2A 2 KCNJ11/R201S Yes nd-MI/3 IAA, GADA, IA-2A, ZnT8A 2 KCNJ11/R201C Yes nd-PD/2 None 3 ABCC8/L213P DEND Yes nd-FI/1 None 15 ABCC8/V324M; ABCC8/W688R Yes nd-CT/2 None 27 - nd-MI/2 ICA, GADA, IA-2A 38 KCNJ11/K170R Yes nd-LE/2 ICA, IAA, GADA, IA-2A 39 - nd-PR/2 None 40 ABCC8/L213P iDEND Yes nd-NA/1 None 40 KCNJ11/R201C Yes + insulin nd-CT/1 none 60 KCNJ11/V59M iDEND Yes nd-NA/2 ICA, GADA, IA-2A 71 ABCC8/A355T Anaemia Yes + insulin nd-MO/3 ICA, IAA, GADA 73 KCNJ11/H46Y Yes nd-RM/4 IAA, GADA, IA-2A 80 - nd-TO/3 GADA, IA-2A 82 - nd-TS/2 None 120 KCNJ11/V59M iDEND Yes nd-RM/6 None 120 KCNJ11/R195Ha nd-RM/5 IAA, GADA, IA-2A 135 KCNJ11/E322K Yes nd-PI/1 ICA 141 - nd-BG/1 GADA 180 ABCC8/S1054Na nd-CES/3 None 190 - Group 2 mdi-RM/3 None 220 KCNJ11/V59M iDEND Yes mdi/NA-B/1 ICA 251 - mdi-PA/1 ICA, IAA, GADA, IA-2A 270 - mdi-RM-OBG/1 IAA, GADA 289 - Muscle hypotrophy mdi-CES/1 ICA, IAA 300 - mdi-RM-OBG/3 IAA, GADA, IA-2A 330 - mdi-RM-OBG/2 IAA, GADA, IA-2A 330 - mdi-NA/2 GADA, IA-2A 354 - SU treatment denotes complete withdrawal of insulin therapy unless specified. Login to comment 72 ABCC8 p.Leu213Pro ABCC8/L213P (c.638T >C) was found to be a de novo mutation in a patient with complete DEND syndrome (nd-PD/2), and in a second proband with iDEND, who had inherited the mutation from her father (Fig. 1), who also presented with iDEND (nd-PR/2). Login to comment 73 ABCC8 p.Leu213Arg A mutation in the same codon, ABCC8/L213R, has been previously reported in association with iDEND [36]. Login to comment 74 ABCC8 p.Val324Met ABCC8 p.Trp688Arg Of our patients, one proband was a compound heterozygote for the ABCC8/V324M mutation, previously described in patients with the transient form of the disease (TNDM) [36], who usually need insulin therapy for less than 1 year [4], and for the novel W688R (c.2062T>G) mutation (nd-FI/1). Login to comment 76 ABCC8 p.Val324Met ABCC8 p.Trp688Arg Because both of the patient`s parents were deceased, we analysed the grandparents` DNA and confirmed the ABCC8/V324M mutation in the maternal grandfather and the ABCC8/ W688R mutation in the paternal grandmother (Fig. 1). Login to comment 77 ABCC8 p.Val324Met ABCC8 p.Trp688Arg After identifying the mutations, an OGTT was done in both patients; the carrier for V324M was diagnosed with diabetes (2 h plasma glucose 14 mmol/l) and the carrier for W688R presented with impaired glucose tolerance (2 h plasma glucose 8.4 mmol/l). Login to comment 78 ABCC8 p.Ala355Thr Finally, a patient carrying the unreported ABCC8/A355T (c.1063G>A; nd-NA/2) variant inherited the mutation from his mother, who was diagnosed with gestational diabetes at the age of 26 years. Login to comment 90 ABCC8 p.Val324Met ABCC8 p.Val324Met ABCC8 p.Trp688Arg ABCC8 p.Trp688Arg V324M T2D 74 years 74 years - W688R IGT 70 years 70 years - V324M/W688R PNDM/MDI 15 days 17 years INS Family nd-FI/1 I. II. III. Login to comment 91 ABCC8 p.Ala355Thr ABCC8 p.Ala355Thr ABCC8 p.Leu213Pro ABCC8 p.Leu213Pro ABCC8 p.Leu213Pro A355T GD 26 years 48 years Family nd-NA/2 A355T PNDM/MDI 71 days 21 years INS I. II. L213P PNDM/MDI 51 days 44 years INS L213P PNDM/MDI 40 days 14 years INS Family nd-PR/2 I. II. Family nd-PD/2 L213P PNDM/MDI 3 days 11 years INS I. II. Fig. 1 Pedigrees of four families with mutations in ABCC8; from top to bottom: mutation, phenotype, age at presentation/diagnosis of diabetes, current age and initial therapy for diabetes. Login to comment 92 ABCC8 p.Val324Met ABCC8 p.Trp688Arg For the two grandparents of proband nd-FI/1, OGTT tests were performed at 70 (W688R) and 74 (V324M) years of age. Login to comment 97 ABCC8 p.Leu213Pro ABCC8 p.Trp688Arg In Group 1, novel mutations in KCNJ11/R201S, ABCC8/L213P and ABCC8/ W688R were identified. Login to comment 98 ABCC8 p.Val324Met The latter was found in a patient who also carried the TNDM-causing ABCC8/V324M mutation [36]. Login to comment 100 ABCC8 p.Val324Met ABCC8 p.Trp688Arg ABCC8 p.Trp688Arg In our case, however, we favour the hypothesis that both ABCC8/V324M and ABCC8/W688R are mildly activating, based on the fact that W688R is associated with impaired glucose tolerance in the paternal grandmother. Login to comment 101 ABCC8 p.Ala355Thr In contrast, we cannot explain at this time the extremely different phenotypes we observed in the carriers of the mutation ABCC8/A355T, who show either PNDM/MDI or gestational diabetes. Login to comment 103 ABCC8 p.Ala355Thr Because the patient with ABCC8/A355T also has a liver-related and haematologic phenotype, it is conceivable that he may carry a mutation in another locus that impacts on glucose metabolism. Login to comment 104 ABCC8 p.Ala355Thr Functional studies are definitely needed to firmly establish the impact of ABCC8/A355T on insulin secretion. Login to comment 116 ABCC8 p.Ala355Thr Conversely, we think that the nine patients in group 1 who had no disease-causing mutation identified, and possibly the patient carrying the ABCC8/A355T mutation, who showed clinical features not associated with mutations to KATP channel genes, are likely to carry a mutation in a locus that has not, as yet, been found. Login to comment