ABCMdb

ABCC8 p.Arg168Cys

Predicted by SNAP2:	A: N (61%), C: N (53%), D: D (80%), E: D (66%), F: D (53%), G: D (66%), H: D (53%), I: N (61%), K: N (53%), L: N (57%), M: N (57%), N: D (66%), P: D (63%), Q: N (61%), S: N (57%), T: N (66%), V: N (72%), W: D (85%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Permanent neonatal diabetes caused by a novel muta... Indian Pediatr. 2012 Jun;49(6):486-8. Jain V, Flanagan SE, Ellard S
Permanent neonatal diabetes caused by a novel mutation.
Indian Pediatr. 2012 Jun;49(6):486-8., [PMID:22796691]

Abstract [show]
Most cases of permanent form of neonatal diabetes mellitus (PNDM) are due to dominant heterozygous gain of function (activating) mutations in either KCNJ11 or ABCC8 genes, that code for Kir 6.2 and SUR1 subunits, respectively of the pancreatic b cell KATP channel. We describe the interesting case of an infant with PNDM, in whom a compound heterozygous activating/ inactivating mutation was found with clinically unaffected parents, each carrying a heterozygous mutation in ABCC8, one predicting gain of function (neonatal diabetes) and the other a loss of function (hyperinsulinemia).

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Sentences [show]
No. Sentence Comment
46 Molecular genetic analysis: Sequencing analysis showed that the infant was heterozygous for two missense mutations, R168C and G1256S, in exons 4 and 31 of the ABCC8 gene. Login to comment
47 The C>T mutation at nucleotide 502 (c.502C>T) results in substitution of cysteine for arginine at codon 168 (p.Arg168Cys) and has been reported previously in a patient with CHI [5].The G>Amutation at nucleotide 3766 (c.3766G>A) results in the substitution of serine for glycine at codon 1256 (p.Gly1256Ser), and has been identified in another patient with PNDM (Flanagan and Ellard, unpublished data). Login to comment
48 Testing of parents showed that the father was heterozygous for the missense mutation G1256S while the mother was heterozygous for the missense mutation R168C, implying that father was a carrier of NDM while mother was a carrier of CHI. Login to comment

[hide] Clinical characteristics and phenotype-genotype an... Eur J Endocrinol. 2014 Jun;170(6):885-92. doi: 10.1530/EJE-14-0045. Epub 2014 Mar 31. Demirbilek H, Arya VB, Ozbek MN, Akinci A, Dogan M, Demirel F, Houghton J, Kaba S, Guzel F, Baran RT, Unal S, Tekkes S, Flanagan SE, Ellard S, Hussain K
Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.
Eur J Endocrinol. 2014 Jun;170(6):885-92. doi: 10.1530/EJE-14-0045. Epub 2014 Mar 31., [PMID:24686051]

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OBJECTIVE: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. DESIGN AND METHODS: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. RESULTS: Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. CONCLUSIONS: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

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Sentences [show]
No. Sentence Comment
67 The remaining six ABCC8 mutations, p.R168C, p.N188S, p.L533P, p.W232G, p.R842Q and p.F591L were each identified in a single patient. Login to comment
85 Gene Current age (year) Exon/intron DNA description Protein description Consequence Transmission Treatment Follow-up Developmental delay Comments Diazoxide responsive Octreotide responsive Pancreatectomy (histology) ABCC8 1 3.9 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide CCC Novel mutation 2 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 3 9.1 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K K K Irregular CCCC Novel mutation 4 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide C Novel mutation 5 0.2 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 6 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K K C (diffuse) Remission 7 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C C (diffuse) Octreotide 8 Died Exon 28 c.3512del p.Leu1171fs Frameshift Heterozygous paternal K K C (diffuse) Died 9 5.8 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC Ectodermal dysplasia 10 9.6 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC 11 0.7 Exon 4 c.502COT c.563AOG p.Arg168Cys/ p.Asn188Ser Missense Compound heterozygous K C C (diffuse) Octreotide K 12 Died Exon 10 c.1598TOC p.Leu533Pro Missense Homozygous K C K Died Novel mutation 13 10.6 Exon 5/ exon 21 c.694TOG/ c.2525GOA p.Trp232Gly/ p.Arg842Gln Missense/ Missense Compound heterozygous K C K Octreotide CC 14 5.5 Exon 12 c.1771TOC p.Phe591Leu Missense Heterozygous C K Diazoxide K KCNJ11 15 2.4 Exon 1 c.101GOA/ c.376GOA p.Arg34His/ p.Glu126Lys Missense/ Missense Compound heterozygous K C K Octreotide K 16 3.3 Exon 1 c.272GOA p.Trp91X Nonsense Homozygous K C C (diffuse) Octreotide CC 17 3.2 Exon 1 c.376GOA p.Glu126Lys Missense Homozygous K C C (diffuse) Octreotide CC HADH 18 4.4 Exon 6 c.706COT p.Arg236X Nonsense Homozygous C Diazoxide C Genotype-phenotype correlation " Comparison between KATP mutation-positive and KATP mutation-negative groups highlighted a statistically significant increased birth weight and younger age of presentation in KATP mutation-positive group as compared with KATP mutation-negative patients (Table 3). Login to comment