ABCMdb

ABCC8 p.Tyr512*

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Publications
[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]

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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.

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No. Sentence Comment
7 In the SUR1 gene mutations, three were nonsense mutations(Y512X,Y1354XandG1469X),onewasaone-basedeletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). Login to comment
49 Exon or intron Nucleotide change Codon Predicted effect Domain Age at onset Birthweight (g) Gestational age (weeks) Therapy Histopathology Long-term outcome Pancreatectomy Diazoxide SUR1 mutation 8 Exon 7 1122delA Q374fs/ter - 1 day 3690 34 - + Sometimes hypoglycaemic 5 Exon 10 C1536A Y512X - 1 day 3635 38 + (80%) - F (tail) N 4 Intron 14 2041-21G → A Aberrant splicing NBD1 1 day 3792 41 + (85%) - F (body) N 6 Intron 29 3653+2T → C Aberrant splicing NBD2 2 months 3470 40 + (80%) - F (tail) N 1 Exon 33 C4062A Y1354X NBD2 1 day 4144 40 + (75-95%) - F (head) N 10 Exon 34 A4153C K1385Q NBD2 1 day 3776 36 - + N 11 Exon 34 A4153C K1385Q NBD2 1 day 4364 38 - + N 12 Exon 36 G4405T G1469X NBD2 3 months 4055 39 + (80%) - F (body) N 2 Intron 36 4415-3G → A Aberrant splicing NBD2 1 day 3803 38 + (80%) - D Insulin-dependent diabetes 13 Exon 37 G4460A R1487K NBD2 1 day 4830 37 + (70%) - F (body) + adenoma N Kir6.2 mutation 14 Exon G101A R34H N terminus 1 day 3104 36 + (95%) - D nd 14 Exon 1032delC C344fs/ter C terminus No mutation 3 2 months 2898 42 + (80%) - F (body) N 7 4 months 3224 40 - + N 9 1 day 2548 39 - + N Nucleotide and codon positions of SUR1 are determined according to the full-length human cDNA sequence incorporating the alternative splice form of exon 17 (GenBank L78207 and L78224). Login to comment
52 The nucleotide sequence substituted an adenine for a cytosine at nt 1536 (Y512X), and a thymine for a guanine at nt 4405 (G1469X). Login to comment