ABCC8 p.Leu135Val
| ClinVar: |
c.404T>C
,
p.Leu135Pro
D
, Pathogenic
|
| Predicted by SNAP2: | A: D (66%), C: D (63%), D: D (85%), E: D (85%), F: N (57%), G: D (80%), H: D (66%), I: N (66%), K: D (85%), M: N (72%), N: D (75%), P: D (85%), Q: D (80%), R: D (85%), S: D (53%), T: D (71%), V: N (57%), W: D (85%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: 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.?
X
ABCC8 p.Leu135Val 20685672:102:475
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.?
X
ABCC8 p.Leu135Val 20685672:105:442
status: NEW