ABCC8 p.Gly716Asp
| ClinVar: |
c.2147G>T
,
p.Gly716Val
D
, Pathogenic
|
| Predicted by SNAP2: | A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (91%), P: D (95%), Q: D (95%), R: D (95%), S: D (91%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| 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] 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
120 Two additional case subjects, with the V715G and G716D mutations, may also be de novo mutations; however, DNA was available on only one of the parents for genetic testing.
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ABCC8 p.Gly716Asp 21536946:120:49
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.Gly716Asp 21536946:148:424
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.Gly716Asp 21536946:189:734
status: NEW[hide] ABCC8 and KCNJ11 molecular spectrum of 109 patient... J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul-Fekete C, de Lonlay P
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.
J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3., [PMID:20685672]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic beta-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
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107 1 DH c-htz This report ABCC8 Exon 16 c.2124_2127delGACT p.Thr709X 1 FH This report ABCC8 Exon 16 c.2147G/A p.Gly716Asp 1 DPET htzm This report ABCC8 Exon 16 c.2153delG p.Gly718fs 1 DH htzP This report ABCC8 Exon 20 c.2425C/T p.Gln809X 1 DH c-htz Damaj et al, 200845 ABCC8 Exon 20 c.2473G/A p.Glu825Lys 1 DPET htzP This report ABCC8 Exon 22 c.2560-?_2697+?del p.Asp854_Trp899del46 1 DH c-htz This report ABCC8 Exon 22 c.2581G/C p.Asp861His 1 DPVS c-htz This report ABCC8 Exon 22 c.2669A/C p.Lys890Thr 1 DH htzP Flanagan et al, 200817 ABCC8 Exon 22 c.2672T/C p.Leu891Pro 1 DH htznovo This report ABCC8 Exon 23 c.2702T/C p.Ile901Thr 2 DH, DPET c-htz This report ABCC8 Exon 23 c.2784G/A p.Trp928X 1 FH This report ABCC8 Exon 23 c.2803C/T p.Gln935X 1 DPET c-htz This report ABCC8 Exon 24 c.2860C/T p.Gln954X 1 FH Flanagan et al, 200817 ABCC8 Intron 24 c.2924-9G/A p.?
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ABCC8 p.Gly716Asp 20685672:107:109
status: NEW119 There is strong evidence that the identified mutation Gly716Asp is pathogenic: (1) it is located in the first nucleotide binding domain, (2) the same residue was reported to be altered (Gly716Val) in a homozygous recessive form of CHI resistant to diazoxide30 and (3) the functional study of Gly716Val showed a reduced surface expression of the mutant channel.31 Among the eight paternally inherited cases, no clinical symptom was reported in the fathers at the time of the child`s diagnosis.
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ABCC8 p.Gly716Asp 20685672:119:54
status: NEW110 1 DH c-htz This report ABCC8 Exon 16 c.2124_2127delGACT p.Thr709X 1 FH This report ABCC8 Exon 16 c.2147G/A p.Gly716Asp 1 DPET htzm This report ABCC8 Exon 16 c.2153delG p.Gly718fs 1 DH htzP This report ABCC8 Exon 20 c.2425C/T p.Gln809X 1 DH c-htz Damaj et al, 200845 ABCC8 Exon 20 c.2473G/A p.Glu825Lys 1 DPET htzP This report ABCC8 Exon 22 c.2560-?_2697+?del p.Asp854_Trp899del46 1 DH c-htz This report ABCC8 Exon 22 c.2581G/C p.Asp861His 1 DPVS c-htz This report ABCC8 Exon 22 c.2669A/C p.Lys890Thr 1 DH htzP Flanagan et al, 200817 ABCC8 Exon 22 c.2672T/C p.Leu891Pro 1 DH htznovo This report ABCC8 Exon 23 c.2702T/C p.Ile901Thr 2 DH, DPET c-htz This report ABCC8 Exon 23 c.2784G/A p.Trp928X 1 FH This report ABCC8 Exon 23 c.2803C/T p.Gln935X 1 DPET c-htz This report ABCC8 Exon 24 c.2860C/T p.Gln954X 1 FH Flanagan et al, 200817 ABCC8 Intron 24 c.2924-9G/A p.?
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ABCC8 p.Gly716Asp 20685672:110:109
status: NEW123 There is strong evidence that the identified mutation Gly716Asp is pathogenic: (1) it is located in the first nucleotide binding domain, (2) the same residue was reported to be altered (Gly716Val) in a homozygous recessive form of CHI resistant to diazoxide30 and (3) the functional study of Gly716Val showed a reduced surface expression of the mutant channel.31 Among the eight paternally inherited cases, no clinical symptom was reported in the fathers at the time of the child`s diagnosis.
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ABCC8 p.Gly716Asp 20685672:123:54
status: NEW