ABCMdb

PMID: 25584046

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., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC8 p.Arg526Cys 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. Login to comment 49 ABCC8 p.Arg526Cys 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. Login to comment 50 ABCC8 p.Arg526Cys Both R526C and c.1879delC (H627Mfs*20) mutations have previously been reported as recessive acting mutations in patients with focal CHI [5]. Login to comment 51 ABCC8 p.Arg526Cys 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. Login to comment 67 ABCC8 p.Arg526Cys Figure 1 Functional characterisation of KATP channels with a heterozygous ABCC8 R526C/H627Mfs*20 compound mutation. Login to comment 76 ABCC8 p.Arg526Cys 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. Login to comment 83 ABCC8 p.Arg1436Gln ABCC8 p.Arg1436Gln ABCC8 p.Asp1193Val 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]. Login to comment 84 ABCC8 p.Arg526Cys Both SUR1 R526C and H627Mfs*20 mutations have been described previously as presumed recessive acting mutations in association with CHI. Login to comment 91 ABCC8 p.Arg526Cys 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. Login to comment 95 ABCC8 p.Arg526Cys 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]. Login to comment