ABCMdb

ABCC8 p.Ala355Thr

Predicted by SNAP2:	C: N (66%), D: D (71%), E: D (71%), F: D (75%), G: N (93%), H: D (66%), I: D (66%), K: D (71%), L: N (53%), M: D (66%), N: D (59%), P: D (71%), Q: D (63%), R: D (66%), S: N (78%), T: N (78%), V: D (66%), W: D (80%), Y: D (66%),
Predicted by PROVEAN:	C: N, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: D,

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[hide] Familial focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2011 Jan;96(1):24-8. Epub 2010 Oct 13. Ismail D, Smith VV, de Lonlay P, Ribeiro MJ, Rahier J, Blankenstein O, Flanagan SE, Bellanne-Chantelot C, Verkarre V, Aigrain Y, Pierro A, Ellard S, Hussain K
Familial focal congenital hyperinsulinism.
J Clin Endocrinol Metab. 2011 Jan;96(1):24-8. Epub 2010 Oct 13., [PMID:20943779]

Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. AIM: We describe the first familial form of focal CHI in two siblings. PATIENTS AND METHODS: The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. CONCLUSION: This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.

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9 An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior sectionoftheheadofthepancreas.Bothsiblingswerefoundtobeheterozygousfortwopaternally inherited ABCC8 mutations, A355T and R1494W. Login to comment
68 Genetics ABCC8 sequencing analysis identified two heterozygous mutations, A355T (c.1063GϾA) and R1494W (c.4480CϾT). Login to comment
70 In contrast, the A355T mutation is novel, and although it affects a residue that is wellconservedacrossspecies,itspathogenicityiscurrently uncertain. Login to comment
74 The heterozygous germ line mutations (A355T; R1494W) are therefore likely to be homozygous within the focal lesion. Login to comment
87 The R1494W mutation is a loss of function mutation that has been identified in at least sixunrelatedprobandswithCHItodate(11).Incontrast,the A355T mutation is novel, and although it affects a residue that is well conserved across species, its pathogenicity is currently uncertain. Login to comment

[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]

Abstract [show]
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
78 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
91 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
101 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 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 Functional studies are definitely needed to firmly establish the impact of ABCC8/A355T on insulin secretion. Login to comment
116 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