ABCC8 p.Ala478Asp
| Predicted by SNAP2: | C: D (66%), D: D (91%), E: D (91%), F: D (85%), G: D (71%), H: D (91%), I: D (80%), K: D (91%), L: D (85%), M: D (71%), N: D (85%), P: D (91%), Q: D (85%), R: D (85%), S: D (63%), T: D (66%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: N, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Diazoxide-unresponsive congenital hyperinsulinism ... Diabetes. 2011 Jun;60(6):1797-804. Epub 2011 May 2. Macmullen CM, Zhou Q, Snider KE, Tewson PH, Becker SA, Aziz AR, Ganguly A, Shyng SL, Stanley CA
Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the beta-cell sulfonylurea receptor SUR1.
Diabetes. 2011 Jun;60(6):1797-804. Epub 2011 May 2., [PMID:21536946]
Abstract [show]
OBJECTIVE: Congenital hyperinsulinemic hypoglycemia is a group of genetic disorders of insulin secretion most commonly associated with inactivating mutations of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (SUR1) and KCNJ11 (Kir6.2). Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with diazoxide, a channel agonist. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. We hypothesized that some medically uncontrollable cases with only one K(ATP) mutation might have dominant, diazoxide-unresponsive disease. RESEARCH DESIGN AND METHODS: Mutations of the K(ATP) genes were identified by sequencing genomic DNA. Effects of mutations on K(ATP) channel function in vitro were studied by expression in COSm6 cells. RESULTS: In 15 families with diazoxide-unresponsive diffuse hyperinsulism, we found 17 patients with a monoallelic missense mutation of SUR1. Nine probands had de novo mutations, two had an affected sibling or parent, and four had an asymptomatic carrier parent. Of the 13 different mutations, 12 were novel. Expression of mutations revealed normal trafficking of channels but severely impaired responses to diazoxide or MgADP. Responses were significantly lower compared with nine SUR1 mutations associated with dominant, diazoxide-responsive hyperinsulinism. CONCLUSIONS: These results demonstrate that some dominant mutations of SUR1 can cause diazoxide-unresponsive hyperinsulinism. In vitro expression studies may be helpful in distinguishing such mutations from dominant mutations of SUR1 associated with diazoxide-responsive disease.
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No. Sentence Comment
97 Direct sequencing of genomic DNA from the proband, his affected mother, and younger brother revealed a single heterozygous A478D mutation in exon 9 of ABCC8 (SUR1) (Fig. 1).
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ABCC8 p.Ala478Asp 21536946:97:123
status: NEW148 Parent of origin Family 1 II-1 LGA 1 No Diffuse Q474R De novo Family 2 II-1 LGA 1 No Diffuse A478D Maternal Family 2 II-2 AGA 1 No Diffuse A478D Maternal Family 3 II-1 AGA 1 No Diffuse V715A Maternal Family 3 II-2 LGA 1 No No surgery V715A Maternal Family 4 II-1 LGA 1 No No surgery V715G Not maternal Family 5 II-1 LGA 1 No Diffuse V715G De novo Family 6 II-1 LGA 42 No Diffuse V715G De novo Family 7 II-1 LGA 5 No Diffuse G716D Not maternal Family 8 II-1 AGA 3 No Diffuse T888P De novo Family 9 II-1 AGA 2 No Diffuse G1384E De novo Family 10 II-1 LGA 1 No Diffuse S1387F De novo Family 11 II-1 LGA 1 No Diffuse S1387Y De novo Family 12 II-1 LGA 1 No Diffuse S1389Y De novo Family 13 II-1 SGA 180 No Diffuse A1458T Paternal Family 14 II-1 LGA 88 No Diffuse Q1459H De novo Family 15 II-1 AGA 167 No Diffuse E1517K Maternal Dominant diazoxide-unresponsive (n = 17) 65% LGA median 1 day range (1-180 days) 100% no Diffuse 5 of 17 maternal 1 of 17 paternal 9 of 17 de novo 2 of 17 not maternal Dominant diazoxide-responsive (n = 13) 77% LGA median 30 days range (1-1,215 days) 100% yes Diffuse 5 of 13 maternal 4 of 13 paternal 4 of 13 de novo Recessive (n = 48) 87% LGA median 1 day range (1-9 days) 100% no Diffuse 48 of 48 biallelic LGA, AGA, SGA 5 large, appropriate, small for gestational age.
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ABCC8 p.Ala478Asp 21536946:148:93
status: NEWX
ABCC8 p.Ala478Asp 21536946:148:139
status: NEW189 The important distinction between dominant and recessive missense mutations of the ABCC8 gene that cause hyperinsulinism appears to be whether they produce SUR1 subunits that can combine with Kir6.2 and then be trafficked to the TABLE 2 Mutant protein biogenesis and activity Surface expression (% of wild-type channel level) MgADP stimulation (% current in 0.1 mmol/L ATP plus 0.5 mmol/L ADP) Diazoxide stimulation (% current in 0.1 mmol/L ATP plus 0.2 mmol/L diazoxide) Mutation 1) Q474R 119.12 6 13.87 3.16 6 1.34 (n = 3) 2.03 6 0.77 (n = 3) 2) A478D 83.67 6 5.33 0.69 6 0.27 (n = 6) 3.14 6 1.37 (n = 3) 3) V715A 83.00 6 5.29 0.53 6 0.28 (n = 3) 1.73 6 0.53 (n = 4) 4) V715G 96.33 6 3.18 0.28 6 0.16 (n = 3) 2.35 6 1.99 (n = 3) 5) G716D 66.67 6 5.24 2.39 6 1.90 (n = 6) 2.37 6 1.32 (n = 4) 6) T888P 54.33 6 5.33 0.38 6 0.30 (n = 3) 1.30 6 0.44 (n = 3) 7) G1384E 101.80 6 8.50 0.17 6 0.09 (n = 4) 1.64 6 0.49 (n = 4) 8) S1387F 83.91 6 5.30 0.84 6 0.17 (n = 4) 4.05 6 1.34 (n = 4) 9) S1387Y 83.13 6 5.38 2.46 6 0.96 (n = 4) 2.44 6 0.42 (n = 4) 10) S1389Y 70.00 6 7.81 1.26 6 0.73 (n = 4) 1.65 + 0.63 (n = 3) 11) A1458T 94.33 6 10.48 0.52 6 0.21 (n = 3) 1.06 6 0.37 (n = 3) 12) Q1459H 91.00 6 2.31 0.69 6 0.39 (n = 3) 1.32 6 0.29 (n = 3) 13) E1517K 72.88 6 5.85 1.73 6 0.39 (n = 3) 1.96 6 0.55 (n = 4) Mean of dominant diazoxide-unresponsive SUR1 mutations 84.6 6 4.64 (n = 13) 1.42 6 0.35 (n = 13)* 1.83 6 0.18 (n = 13)† Mean of dominant diazoxide-responsive SUR1 mutations 93.68 6 5.07 (n = 10) 14.52 6 5.15 (n = 10) 18.33 6 6.06 (n = 10) Wild type 100 61.19 6 5.53 (n = 11) 77.8 6 2.2 (n = 9) Data are means 6 SE.
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ABCC8 p.Ala478Asp 21536946:189:548
status: NEW[hide] Molecular genetic testing of patients with monogen... Mol Genet Metab. 2015 Mar;114(3):451-8. doi: 10.1016/j.ymgme.2014.12.304. Epub 2014 Dec 20. Bennett JT, Vasta V, Zhang M, Narayanan J, Gerrits P, Hahn SH
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism.
Mol Genet Metab. 2015 Mar;114(3):451-8. doi: 10.1016/j.ymgme.2014.12.304. Epub 2014 Dec 20., [PMID:25555642]
Abstract [show]
Genetic sequencing has become a critical part of the diagnosis of certain forms of pancreatic beta cell dysfunction. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenicity of variants remains a challenge, and requires sharing of sequence and phenotypic data between laboratories. We reviewed all diabetes and hyperinsulinism-associated molecular testing done at the Seattle Children's Molecular Genetics Laboratory from 2009 to 2013. 331 probands were referred to us for molecular genetic sequencing for Neonatal Diabetes (NDM), Maturity-Onset Diabetes of the Young (MODY), or Congenital Hyperinsulinism (CHI) during this period. Reportable variants were identified in 115 (35%) patients with 91 variants in one of 6 genes: HNF1A, GCK, HNF4A, ABCC8, KCNJ11, or INS. In addition to identifying 23 novel variants, we identified unusual mechanisms of inheritance, including mosaic and digenic MODY presentations. Re-analysis of all reported variants using more recently available databases led to a change in variant interpretation from the original report in 30% of cases. These results represent a resource for molecular testing of monogenic forms of diabetes and hyperinsulinism, providing a mutation spectrum for these disorders in a large North American cohort. In addition, they highlight the importance of periodic review of molecular testing results.
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120 Gene Nucleotide Protein Pheno dbSNP Times seen Interp. LOVD ClinVar Reference ABCC8 c.1277ANG/c.3545GNA p.N426S/p.R1182Q NDM -/rs193922400 1/2 VUS/PATH -/- -/LP This report/[9] c.1433CNA p.A478D CHI - 1 PATH - - [41] c.1608TNG p.F536L NDM - 1 LP - - This report c.2422CNA p.Q808K "DM1"* rs202189540 1 LB - - This report c.2506CNT/c.4138_4140delinsCA p.R836*/p.T1380Qfs*80 CHI rs72559722/- 1/1 PATH/PATH -/- -/- [42]/this report c.3976GNA p.E1326K CHI rs200563930 1 VUS - - [8] ex 32 del p.?
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ABCC8 p.Ala478Asp 25555642:120:189
status: NEW