ABCC8 p.Gly1342Glu
| Predicted by SNAP2: | A: D (71%), C: D (75%), D: D (85%), E: D (85%), F: D (85%), H: D (85%), I: D (85%), K: D (91%), L: D (85%), M: D (80%), N: D (80%), P: D (85%), Q: D (85%), R: D (91%), S: D (75%), T: D (80%), V: D (80%), W: D (85%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: 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, W: D, Y: D, |
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[hide] Hyperinsulinism of infancy: novel ABCC8 and KCNJ11... J Clin Endocrinol Metab. 2004 Dec;89(12):6224-34. Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, Nesher Y, Kuchinski N, Ben-Shushan E, Shatz O, Nahari E, Potikha T, Zangen D, Tenenbaum-Rakover Y, de Vries L, Argente J, Gracia R, Landau H, Eliakim A, Lindley K, Dunne MJ, Aguilar-Bryan L, Glaser B
Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
J Clin Endocrinol Metab. 2004 Dec;89(12):6224-34., [PMID:15579781]
Abstract [show]
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
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No. Sentence Comment
72 Photolabeling and surface expression After an overnight incubation after electroporation, whole-cell photolabeling (25) and surface expression assays were performed as pre- TABLE1.Patientclinicaldata Patientno.Ethnicity Ageat diagnosis Responsive todiazoxide Responsive tooctreotide PancreatectomyHistologyElectrophysiologyFamilyhistoryMutationsidentified 1BengalBirthNoNoYesDiffuseKATPchannelopathyNo3992-9g3a (homozyg) 2BedouinBirthPartialPartialYesDiffuseNotdoneYesR836X(homozyg) 3IndiaBirthNoPartialYesDiffuseKATPchannelopathyNoG111R(homozyg) 4ArabBirthNoNoYesDiffuseNotdoneNoR1494W (homozyg) 5CaucasianBirthNoPartialYesDiffuseKATPchannelopathyNoG70Eand R1419H 6CaucasianBirthNoPartialYesDiffuseKATPchannelopathyNo2154ϩ3a3gand G1342E 7ArabBirthNoPartialYesDiffuseNotdoneNo1113insT (homozyg) 8ArabBirtha NoPartialYesDiffuseNotdoneYesP254L(homozyg) 9Bedouin2dPartialYesNoNotdoneCousinwithtransient neonatal hypoglycemia ϩ88g3t (homozyg) 10CaucasianBirthNoPartialYesDiffuseKATPchannelopathyYes(sister)2154ϩ3a3g (heterozyg) 11Caucasian3dNoNoYesDiffuseNotdoneNo-64c3g (heterozyg) 12AshkenaziJewishBirthNoPartialNoNotdoneNoNone 13MixedAshkenazi- SepharadicJewish 4-6monthsResponsiveNottestedNoNotdoneNoNone 14Caucasian4-6monthsNoNoYesDiffuseNodefectsNoNone 15CaucasianBirthYesNottestedNoNotdoneYesNone Homozyg,Homozygous;heterozyg,heterozygous.
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ABCC8 p.Gly1342Glu 15579781:72:738
status: NEW94 Patient 6 inherited this mutation on the maternal allele and was found to have a second mutation (G1342E) on the paternal allele (Table 2).
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ABCC8 p.Gly1342Glu 15579781:94:98
status: NEW101 ABCC8 -64 c3g Promoter gcc gcc ccc Promoter 11 gGc G70E 2 ccc ggg cac Missense 5 gAg G111R 3 gcc ggg atg Missense 3 Agg 2154 ϩ 3a3g Intron 15 agg tat ggc Splice-site 6, 10 tGt R836X 21 cag cga atc Nonsense 2 Tga 1113 ins T 27 ttt ttt gag Single-base insertion 7 ttt ttt Tga 3992-9 g3a Intron 32 cgc aag cgt Splice-site 1 aaA G1342E 33 caa ggg aag Missense 6 gAg R1419H 35 ctg cgc tca Missense 5 cAc R1494W 37 gcc cgg gcc Missense 4 Tgg KCBJ11 ϩ88 g3t Promoter gaa gtg agg Promoter 9 Ttg P254L Exon 1 gcc cCg ctg Missense 8 cTg a For each mutation, the upper line indicates the wt sequence, and the lower line indicates the mutant sequence.
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ABCC8 p.Gly1342Glu 15579781:101:331
status: NEW