ABCMdb

ABCC8 p.Trp688Arg

Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (85%), E: D (85%), F: D (80%), G: D (85%), H: D (91%), I: D (80%), K: D (91%), L: D (80%), M: D (85%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (80%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, Y: D,

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[hide] Permanent diabetes during the first year of life: ... Diabetologia. 2011 Jul;54(7):1693-701. Epub 2011 Mar 10. 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., [PMID:21544516]

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AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

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41 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
74 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 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 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
90 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
92 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 In Group 1, novel mutations in KCNJ11/R201S, ABCC8/L213P and ABCC8/ W688R were identified. Login to comment
100 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