ABCC8 p.Arg526Cys
| Predicted by SNAP2: | A: D (80%), C: D (75%), D: D (91%), E: D (91%), F: D (85%), G: D (85%), H: D (80%), I: D (80%), K: D (80%), L: D (80%), M: D (80%), N: D (80%), P: D (91%), Q: D (80%), S: D (80%), T: D (80%), V: D (80%), W: D (80%), Y: D (85%), |
| 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] 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
6 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.
X
ABCC8 p.Arg526Cys 25584046:6:90
status: NEW49 Results Sequence analysis identified biallelic ABCC8 mutation in the proband - a missense mutation, R526C, inherited from an unaffected mother and a frameshift mutation, c.1879delC (H627Mfs*20), inherited from an unaffected father.
X
ABCC8 p.Arg526Cys 25584046:49:100
status: NEW50 Both R526C and c.1879delC (H627Mfs*20) mutations have previously been reported as recessive acting mutations in patients with focal CHI [5].
X
ABCC8 p.Arg526Cys 25584046:50:5
status: NEW51 Functional analysis of mutant channels Methods Single point mutations (R526C and c.1879delC) were introduced into the hamster SUR1 clone by PCR using the Strategene XL Mutagenesis Kit according to the manufacturer`s instructions.
X
ABCC8 p.Arg526Cys 25584046:51:71
status: NEW67 Figure 1 Functional characterisation of KATP channels with a heterozygous ABCC8 R526C/H627Mfs*20 compound mutation.
X
ABCC8 p.Arg526Cys 25584046:67:80
status: NEW76 Subsequent follow-up revealed persistent requirement for diazoxide to control CHI. Functional analysis of the mutant KATP channel subunits confirmed a phenotype of diazoxide-responsive CHI in association with ABCC8 R526C/H627Mfs*20 compound heterozygous mutation.
X
ABCC8 p.Arg526Cys 25584046:76:215
status: NEW84 Both SUR1 R526C and H627Mfs*20 mutations have been described previously as presumed recessive acting mutations in association with CHI.
X
ABCC8 p.Arg526Cys 25584046:84:10
status: NEW91 As the frameshift mutation H627Mfs*20 results in a premature termination codon and is likely to be degraded by non-sense mediated decay, it is possible that the KATP channels in double mutant SUR1R256C/H627Mfs*20 will contain SUR1 subunits produced by allele carrying R526C mutation only and hence the response shown by the SUR1R256C/H627Mfs*20 resembles that of SUR1R256C mutant.
X
ABCC8 p.Arg526Cys 25584046:91:268
status: NEW95 Our functional data, however, is not consistent with the previous observation of diazoxide-unresponsive focal CHI in association with paternally inherited heterozygous ABCC8 R526C mutation [5].
X
ABCC8 p.Arg526Cys 25584046:95:174
status: NEW