ABCC8 p.Tyr179Cys
| Predicted by SNAP2: | A: D (59%), C: D (63%), D: D (59%), E: D (75%), F: D (66%), G: N (53%), H: D (63%), I: D (71%), K: D (71%), L: D (71%), M: D (71%), N: N (61%), P: D (75%), Q: D (63%), R: D (80%), S: N (53%), T: D (59%), V: D (66%), W: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: N, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, |
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[hide] ABCC8 and KCNJ11 molecular spectrum of 109 patient... J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul-Fekete C, de Lonlay P
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.
J Med Genet. 2010 Nov;47(11):752-9. Epub 2010 Aug 3., [PMID:20685672]
Abstract [show]
BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic beta-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.
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102 J Med Genet 2010;47:752e759. doi:10.1136/jmg.2009.075416 Original article Table 2 Characteristics of ABCC8 and KCNJ11 mutations Gene Location Nucleotide sequence change Protein effect Occurrence Histopathological / radiological diagnosisz Genetic Statusy References ABCC8 Exon 1 c.62T/A p.Val21Asp 1 DPVS hmz Sandal et al, 200944 ABCC8 Exon 2 c.221G/A p.Arg74Gln 1 DH c-htz Flanagan et al, 200817 ABCC8 Exon 2 c.259_268del p.Cys87fs 1 FH This report ABCC8 Exon 3 c.403C/G p.Leu135Val 1 DH c-htz This report ABCC8 Exon 4 c.428G/A p.Trp143X 3 FH, DH, DPET c-htz (x2) This report ABCC8 Exon 4 c.496C/T p.Gln166X 1 DPET c-htz This report ABCC8 Exon 4 c.536A/G p.Tyr179Cys 2 FH, DPET hmz Damaj et al, 200845 ABCC8 Intron 4 c.580-1G/C p.?
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ABCC8 p.Tyr179Cys 20685672:102:659
status: NEW105 3 FH (x2), DPET htzP Flanagan et al, 2008 ABCC8 Exon 12 c.1732_1746dup15 p.Ala578_Leu582dup5 1 DPET htzP Flanagan et al, 200817 ABCC8 Exon 12 c.1738C/T p.Leu580Phe 1 DPET hmz This report ABCC8 Exon 12 c.1792C/T p.Arg598X 2 FH, DH c-htz Flanagan et al, 200817 ABCC8 Intron 13 c.1923+5G/T p.?
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ABCC8 p.Tyr179Cys 20685672:105:626
status: NEW[hide] Chromosome 11p15 paternal isodisomy in focal forms... J Clin Endocrinol Metab. 2008 Dec;93(12):4941-7. Epub 2008 Sep 16. Damaj L, le Lorch M, Verkarre V, Werl C, Hubert L, Nihoul-Fekete C, Aigrain Y, de Keyzer Y, Romana SP, Bellanne-Chantelot C, de Lonlay P, Jaubert F
Chromosome 11p15 paternal isodisomy in focal forms of neonatal hyperinsulinism.
J Clin Endocrinol Metab. 2008 Dec;93(12):4941-7. Epub 2008 Sep 16., [PMID:18796520]
Abstract [show]
CONTEXT: Focal forms of congenital hyperinsulinism are due to a constitutional heterozygous mutation of paternal origin in the ABCC8 gene, more often than the KCNJ11 gene, located in the 11p15.1 region. This mutation is associated with the loss of the maternally inherited 11p15.1 to 11p15.5 region in the lesion. We investigated the possible occurrence of a compensatory duplication of the paternal 11p15.1-11p15.5 region. MATERIALS AND METHODS: A combined immunohistochemistry and fluorescent in situ hybridization study on beta-cell interphase nuclei with probes covering two genes located in this region (ABCC8 and CDKN1C genes) was performed in four cases of focal forms of hyperinsulinism. RESULTS: beta-Cells in the lesions of four cases of focal congenital hyperinsulinism were diploid for chromosomes 11 and 13. The 11p15.1 to 11p15.2 and 11p15.4 to 11p15.5 regions containing ABCC8 and CDKN1C genes, respectively, were present with two copies. Loss of the maternal allele was confirmed in these focal lesions with microsatellite markers flanking the ABCC8 and CDKN1C genes, whereas a heterozygous mutation in the ABCC8 gene was inherited from the father. CONCLUSIONS: There is a duplication of the paternal allele on chromosome 11 in the focal forms of hyperinsulinism lesion. The paternal isodisomy observed rendered the beta-cells homozygous for ABCC8 mutation and harbored a K-channel defect in the lesion similar to that observed in diffuse forms of congenital hyperinsulinism.
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58 Four focal and two diffuse forms of neonatal hyperinsulinism are studied Case CHI type Gene Location Nucleotide change Protein effect 1 FoCHI ABCC8 Exon 33 c.4040_4045del p.Ile1347_Gln1348del 2 FoCHI ABCC8 Exon 8 c.1331AϾG p.Gln144Arg 3 FoCHI ABCC8 Intron 32 c.3992-9GϾA p.?, aberrant splicing 4 FoCHI ABCC8 Exon 4 c.536AϾG p.Tyr179Cys 5 DiCHI ABCC8 Exons 12 and 20 ͓c.1792CϾT͔ϩ͓c.2425CϾT͔ ͓p.Arg598ter͔ϩ͓p.Gln809X͔ 6 DiCHI NA ABCC8 mutation was proven for the four focal form cases and one of the diffuse form cases.
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ABCC8 p.Tyr179Cys 18796520:58:344
status: NEW