ABCC8 p.Arg1436Gln
Predicted by SNAP2: | A: D (80%), C: D (80%), D: D (95%), E: D (91%), F: D (91%), G: D (91%), H: D (85%), I: D (85%), K: D (75%), L: D (85%), M: D (80%), N: D (85%), P: D (91%), Q: D (75%), S: D (80%), T: D (85%), V: D (85%), W: D (91%), Y: D (91%), |
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, S: D, T: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Complex ABCC8 DNA variations in congenital hyperin... Clin Endocrinol (Oxf). 2007 Jul;67(1):115-24. Epub 2007 Apr 27. Muzyamba M, Farzaneh T, Behe P, Thomas A, Christesen HB, Brusgaard K, Hussain K, Tinker A
Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies.
Clin Endocrinol (Oxf). 2007 Jul;67(1):115-24. Epub 2007 Apr 27., [PMID:17466004]
Abstract [show]
OBJECTIVE: Congenital hyperinsulinism (CHI) is a cause of persistent and severe hypoglycaemia in infancy. Mutations in the genes ABCC8 and KCNJ11 encoding SUR1 and Kir6.2, respectively, are the commonest cause of CHI. We investigated whether the possession of two DNA variants leading to coding changes in a single allele of ABCC8 can affect the potential mechanism of disease pathogenesis. DESIGN AND PATIENTS: We studied two patients with complex mutations in the ABCC8 gene with CHI and used in vitro studies to explore the potential disease mechanism and the contribution of the various mutant allelles. RESULTS: The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1. Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional. Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex. In a second family, the patient had histologically focal disease and was heterozygous for two mutations from his father (G228D and D1471N) and one from his mother (V1572I). SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. By contrast, V1572I is trafficked appropriately and is functional, consistent with a mechanism of reduction to hemizygosity of paternal ABCC8 in focal disease. V1572I is likely to be a benign DNA variant. CONCLUSION: In one patient the combination of two coding variants led to intracellular retention of channel complex. In a second patient, functional studies allowed us to unravel the DNA variants likely to be causing the abrogation of ATP-sensitive K(+) channel function.
Comments [show]
None has been submitted yet.
No. Sentence Comment
3 Results The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1.
X
ABCC8 p.Arg1436Gln 17466004:3:91
status: NEW4 Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional.
X
ABCC8 p.Arg1436Gln 17466004:4:126
status: NEW5 Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex.
X
ABCC8 p.Arg1436Gln 17466004:5:40
status: NEW30 There is also a notation based on a potential splice variant of 1582 amino acids in length.19 The SUR1 mutations,D1193V and R1436Q (referred to as SUR1D1193V/R1436Q), and G228D and D1471 (referred to as SUR1G228D/D1471N),were made in the same SUR1 cDNA construct to mimic the fact that the patients had mutations on the same chromosome.Mouse Kir6·2 was used and expressed as described previously.41 Mouse Kir6·2-GFP (Kir6·2 fused in frame with the enhanced variant of the green fluorescent protein) and Kir6·2-HA (Kir6·2 engineered to contain an extracellular antigenic haemagglutinin epitope tag between the first transmembrane domain and the H5 segment) were kind gifts of Drs Ribalet and Jan, respectively.
X
ABCC8 p.Arg1436Gln 17466004:30:124
status: NEWX
ABCC8 p.Arg1436Gln 17466004:30:158
status: NEW64 He was homozygous for two mutations in SUR1, namely D1193V and R1436Q, with both mutations occurring on each allele.
X
ABCC8 p.Arg1436Gln 17466004:64:63
status: NEW93 In particular, SUR1D1193V/R1436Q was less efficiently transfected.
X
ABCC8 p.Arg1436Gln 17466004:93:26
status: NEW95 In addition, in HEK293 cells we have not established a clear correlation between glycosylation pattern and trafficking status.48 We next examined the behaviour of SUR1D1193V, SUR1R1436Q and SUR1D1193V/R1436Q.
X
ABCC8 p.Arg1436Gln 17466004:95:201
status: NEW103 We next examined the behaviour of SUR1D1193V, SUR1R1436Q and SUR1D1193V/R1436Q.
X
ABCC8 p.Arg1436Gln 17466004:103:72
status: NEW114 SUR1D1193V and SUR1V1572I were functional in Rb86 flux assays whereas SUR1R1436Q, SUR1D1193V/R1436Q,SUR1G228D,SUR1D1471NandSUR1G228D/ D1471N were not (Fig. 4).
X
ABCC8 p.Arg1436Gln 17466004:114:93
status: NEW120 SUR1D1193V, SUR1V1572I and SUR1D1471N were functional in patch clamp assays whereas SUR1R1436Q, SUR1D1193V/R1436Q, SUR1G228D and SUR1G228D/D1471N were not.In the knowledge of these results we repeated the flux assays and trafficking assays with Kir6·2-GFP with SUR1D1471N.
X
ABCC8 p.Arg1436Gln 17466004:120:107
status: NEW128 Patient 1 had severe diffuse disease and was homozygous for two ABCC8 mutations in the cis configuration (SUR1D1193V/ R1436Q).
X
ABCC8 p.Arg1436Gln 17466004:128:118
status: NEW141 The R1436Q mutation led to channel complexes present at the plasma membrane; however,under our assay conditions we were not able to demonstrate significant channel activity.
X
ABCC8 p.Arg1436Gln 17466004:141:4
status: NEW[hide] Genotypes of the pancreatic beta-cell K-ATP channe... Clin Endocrinol (Oxf). 2005 Apr;62(4):458-65. Ohkubo K, Nagashima M, Naito Y, Taguchi T, Suita S, Okamoto N, Fujinaga H, Tsumura K, Kikuchi K, Ono J
Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy.
Clin Endocrinol (Oxf). 2005 Apr;62(4):458-65., [PMID:15807877]
Abstract [show]
OBJECTIVE: Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic beta-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic beta-cell ATP-sensitive potassium channel. PATIENTS AND METHODS: In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease. RESULTS: We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter). CONCLUSION: The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.
Comments [show]
None has been submitted yet.
No. Sentence Comment
122 To date, only three kinds of SUR1 mutations (I446fsdelT, R1420C and R1436Q) have been reported in Japanese PHHI patients.20,42 We defined 11 novel mutations, and the SUR1 and Kir6.2 mutations account for about 80% of the PHHI cases in this study, although Tanizawa et al.20 reported only about 20% (three kinds of mutations in four patients from the screening of 17 PHHI patients) and Someya et al.42 did not detect any mutations (in eight PHHI patients).
X
ABCC8 p.Arg1436Gln 15807877:122:68
status: NEW[hide] Genetic analysis of Japanese patients with persist... Diabetes. 2000 Jan;49(1):114-20. Tanizawa Y, Matsuda K, Matsuo M, Ohta Y, Ochi N, Adachi M, Koga M, Mizuno S, Kajita M, Tanaka Y, Tachibana K, Inoue H, Furukawa S, Amachi T, Ueda K, Oka Y
Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1.
Diabetes. 2000 Jan;49(1):114-20., [PMID:10615958]
Abstract [show]
To elucidate the genetic etiology of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the Japanese population, we conducted a polymerase chain reaction-single-strand conformation polymorphism analysis of the sulfonylurea receptor 1 (SUR1) and Kir6.2 genes in 17 Japanese PHHI patients, including a pair of siblings from a consanguineous family. We also analyzed the glutamate dehydrogenase gene for the exons encoding an allosteric regulatory domain of the enzyme. In the SUR1 gene, we identified one frameshift (I446fsdelT) and two missense (R1420C, R1436Q) mutations. None of these mutations were found in control Japanese subjects. Siblings homozygous for the R1420C mutation had a mild form, whereas two patients heterozygous for the I446fsdelT and R1436Q mutations, respectively, exhibited a severe form of PHHI. Functional consequences of these mutations on K(ATP) function were evaluated using 86Rb+ efflux studies in COS-7 cells. SUR1-446fsdelT and SUR1-1436Q did not form a functional K(ATP). Western blot analysis after transient expression in COS-7 cells revealed the expression of SUR1-1436Q protein to be markedly reduced, suggesting SUR1-1436Q to be unstable in these cells. K(ATP)(SUR1-1420C) showed reduced responses to metabolic inhibition by oligomycin and 2-deoxyglucose. K(ATP) channels are under complex regulation by intracellular ATP and ADP. ATP both inhibits and activates these channels. The inhibition is probably mediated through direct ATP interaction with a pore-forming subunit Kir6.2, whereas the activation is likely to be through a regulatory subunit SUR1. There is a cooperative regulation of ATP and ADP binding to SUR1, and this cooperativity may be involved in regulating the K(ATP) channel. In SUR1-1420C, high-affinity binding of ATP to the nucleotide-binding fold (NBF)-1 was indistinguishable from that of wild-type SUR1. However, stabilization of ATP binding to NBF-1 by MgATP or MgADP was impaired, suggesting that this defect may account for impaired K(ATP)(SUR1-1420C) function. This is the first direct biochemical evidence that the cooperativity of nucleotide binding to SUR1 is impaired in a SUR1 mutant causing PHHI. No mutations were identified in the Kir6.2 and glutamate dehydrogenase genes. The genetic etiology of PHHI appears to be heterogeneous. SUR1 mutations may account for no more than 20% of PHHI cases in Japanese patients. Mutations of Kir6.2 and glutamate dehydrogenase genes are likely to be even less common.
Comments [show]
None has been submitted yet.
No. Sentence Comment
2 In the SUR1 gene, we identified one frameshift (I446fsdelT) and two missense (R1420C, R1436Q) mutations.
X
ABCC8 p.Arg1436Gln 10615958:2:86
status: NEW4 Siblings homozygous for the R1420C mutation had a mild form, whereas two patients heterozygous for the I446fsdelT and R1436Q mutations, respectively, exhibited a severe form of PHHI.
X
ABCC8 p.Arg1436Gln 10615958:4:118
status: NEW63 The R1436Q mutation created a BsrI restriction site (CCAGTG).
X
ABCC8 p.Arg1436Gln 10615958:63:4
status: NEW64 After PCR amplification of exon9 (I446fsdelT)or exon 35 (R1420Cand R1436Q), the products were digested with the appropriate restriction enzymes and analyzed by electrophoresis on 2% agarose gel.
X
ABCC8 p.Arg1436Gln 10615958:64:67
status: NEW67 Site-directed mutagenesis was performed using mutagenesis primers (for I446fsdelT: 5 -acg ctc cgt tca tgc ctc tcc atc atc c-3 ; for R1420C: 5 -gcc agt aca gat cat gtg ggc gtg atc ctc c-3 ; and for R1436Q: 5 -ttc agc ggc acc atc caa ttc aacctg gac cc-3 ) and a GeneEditor in vitro Site-DirectedMuta- genesisSystem (Promega, Madison, WI).
X
ABCC8 p.Arg1436Gln 10615958:67:197
status: NEW81 We identified three potential disease-causing mutations (I446fsdelT, R1420C, and R1436Q).
X
ABCC8 p.Arg1436Gln 10615958:81:81
status: NEW90 Two other mutations (R1420C and R1436Q) were missense mutations, both in NBF-2, a functionally important domain of SUR1.
X
ABCC8 p.Arg1436Gln 10615958:90:32
status: NEW95 R1436Q is a novel missense mutation.
X
ABCC8 p.Arg1436Gln 10615958:95:0
status: NEW120 Therefore, we introduced I446fsdelT, R1420C, and R1436Q mutations by site-directed mutagenesis to the corresponding positions of mouse SUR1 cDNA, and mutant SUR1 and mouse Kir6.2 were transiently coexpressed in COS-7 cells to reconstitute the mutant KATP channel.
X
ABCC8 p.Arg1436Gln 10615958:120:49
status: NEW124 Because the R1436Q mutation is a missense mutation, the protein expression level of SUR1-1436Q was assessed by Western blot analysis.
X
ABCC8 p.Arg1436Gln 10615958:124:12
status: NEW128 Activation ofthe channel by diazoxide also appeared to be impaired in the KATP(SUR1-1420C) mutant, TABLE 3 Profiles of patients with SUR1 gene mutations Onset Birth Treatment/ Patient Mutation (day) weight (g) outcome 1 I446fsdelT 0 5,014 Partial pancreatectomy 2 R1420C 0 5,254 Remission 3 R1420C 0 5,080 Remission 4 R1436Q 0 3,410 Partial pancreatectomy FIG. 1.
X
ABCC8 p.Arg1436Gln 10615958:128:318
status: NEW160 This may also be the case for patient 4, who was heterozygous for a germline R1436Q mutation.
X
ABCC8 p.Arg1436Gln 10615958:160:77
status: NEW66 Site-directed mutagenesis was performed using mutagenesis primers (for I446fsdelT: 5 -acg ctc cgt tca tgc ctc tcc atc atc c-3 ; for R1420C: 5 -gcc agt aca gat cat gtg ggc gtg atc ctc c-3 ; and for R1436Q: 5 -ttc agc ggc acc atc caa ttc aacctg gac cc-3 ) and a GeneEditor in vitro Site-DirectedMuta- genesisSystem (Promega, Madison, WI).
X
ABCC8 p.Arg1436Gln 10615958:66:197
status: NEW80 We identified three potential disease-causing mutations (I446fsdelT, R1420C, and R1436Q).
X
ABCC8 p.Arg1436Gln 10615958:80:81
status: NEW89 Two other mutations (R1420C and R1436Q) were missense mutations, both in NBF-2, a functionally important domain of SUR1.
X
ABCC8 p.Arg1436Gln 10615958:89:32
status: NEW94 R1436Q is a novel missense mutation.
X
ABCC8 p.Arg1436Gln 10615958:94:0
status: NEW119 Therefore, we introduced I446fsdelT, R1420C, and R1436Q mutations by site-directed mutagenesis to the corresponding positions of mouse SUR1 cDNA, and mutant SUR1 and mouse Kir6.2 were transiently coexpressed in COS-7 cells to reconstitute the mutant KATP channel.
X
ABCC8 p.Arg1436Gln 10615958:119:49
status: NEW123 Because the R1436Q mutation is a missense mutation, the protein expression level of SUR1-1436Q was assessed by Western blot analysis.
X
ABCC8 p.Arg1436Gln 10615958:123:12
status: NEW127 Activation ofthe channel by diazoxide also appeared to be impaired in the KATP(SUR1-1420C) mutant, TABLE 3 Profiles of patients with SUR1 gene mutations Onset Birth Treatment/ Patient Mutation (day) weight (g) outcome 1 I446fsdelT 0 5,014 Partial pancreatectomy 2 R1420C 0 5,254 Remission 3 R1420C 0 5,080 Remission 4 R1436Q 0 3,410 Partial pancreatectomy FIG. 1.
X
ABCC8 p.Arg1436Gln 10615958:127:318
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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
121 "Hypoglycemia"* - 1 PATH - - [15] c.4135CNA p.R1379S NDM rs137852673 1 PATH - PATH ClinVar c.4307GNA p.R1436Q n.p. rs387906407 2 PATH PATH PATH [43] c.4543ANG p.T1515A CHI - 1 LP - - This report KCNJ11 c.137ANG p.H46R NDM - 1 PATH - - [44] c.143ANT p.N48I NDM - 2 PATH - - [25] c.497GNA p.C166Y NDM rs80356618 1 PATH - PATH [45] c.601CNT p.R201C NDM rs80356625 1 PATH - PATH [17] c.602GNA p.R201H NDM rs80356624 1 PATH VUS - [45] c.616CNT p.R206C CHI - 1 LP - - This report c.637GNA p.A213T CHI - 1 PATH - - [46] c.685GNA p.E229K NDM - 1 PATH - - [30] c.691GNC/c.970GNA p.V231L/p.G324R NDM -/- 1/1 VUS/VUS -/- -/- This report/this report INS c.-331delC p.?
X
ABCC8 p.Arg1436Gln 25555642:121:103
status: NEW[hide] Congenital hyperinsulinism: clinical and molecular... Int J Pediatr Endocrinol. 2014;2014(1):24. doi: 10.1186/1687-9856-2014-24. Epub 2014 Dec 15. Arya VB, Aziz Q, Nessa A, Tinker A, Hussain K
Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy.
Int J Pediatr Endocrinol. 2014;2014(1):24. doi: 10.1186/1687-9856-2014-24. Epub 2014 Dec 15., [PMID:25584046]
Abstract [show]
BACKGROUND: Mutations in ABCC8 and KCNJ11 are the most common cause of congenital hyperinsulinism (CHI). Recessive as well as dominant acting ABCC8/KCNJ11 mutations have been described. Diazoxide, which is the first line medication for CHI, is usually ineffective in recessive ABCC8 mutations. We describe the clinical and molecular characterisation of a recessive ABCC8 mutation in a CHI patient that is diazoxide response. CLINICAL CASE: A term macrosomic female infant presented with symptomatic persistent hypoglycaemia confirmed to be secondary to CHI. She exhibited an excellent response to moderate doses of diazoxide (10 mg/kg/day). Molecular genetic analysis of the proband confirmed a biallelic ABCC8 mutation - missense R526C inherited from an unaffected mother and a frameshift c.1879delC mutation (H627Mfs*20) inherited from an unaffected father. Follow-up highlighted persistent requirement for diazoxide to control CHI. Functional analysis of mutants confirmed them to result in diazoxide-responsive CHI, consistent with the clinical phenotype. CONCLUSION: Biallelic ABCC8 mutations may result in diazoxide-responsive CHI. Irrespective of the molecular genetic analysis results, accurate assessment of the response to diazoxide should be undertaken before classifying a patient as diazoxide-responsive or unresponsive CHI.
Comments [show]
None has been submitted yet.
No. Sentence Comment
83 Muzyamba et al. showed that single SUR1 mutants (D1193V or R1436Q) trafficked to the plasma membrane whereas the double mutant (SUR1D1193V/ R1436Q) was retained in the endoplasmic reticulum [16].
X
ABCC8 p.Arg1436Gln 25584046:83:59
status: NEWX
ABCC8 p.Arg1436Gln 25584046:83:140
status: NEW