ABCC8 p.Ala390Glu
| Predicted by SNAP2: | C: N (57%), D: D (66%), E: D (66%), F: D (59%), G: D (63%), H: D (63%), I: D (63%), K: D (66%), L: D (63%), M: D (59%), N: D (59%), P: D (75%), Q: D (59%), R: D (63%), S: N (61%), T: D (53%), V: D (63%), W: D (75%), Y: D (71%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Whole genome SNP genotyping and exome sequencing r... PLoS One. 2013 Jul 15;8(7):e68740. doi: 10.1371/journal.pone.0068740. Print 2013. Proverbio MC, Mangano E, Gessi A, Bordoni R, Spinelli R, Asselta R, Valin PS, Di Candia S, Zamproni I, Diceglie C, Mora S, Caruso-Nicoletti M, Salvatoni A, De Bellis G, Battaglia C
Whole genome SNP genotyping and exome sequencing reveal novel genetic variants and putative causative genes in congenital hyperinsulinism.
PLoS One. 2013 Jul 15;8(7):e68740. doi: 10.1371/journal.pone.0068740. Print 2013., [PMID:23869231]
Abstract [show]
Congenital hyperinsulinism of infancy (CHI) is a rare disorder characterized by severe hypoglycemia due to inappropriate insulin secretion. The genetic causes of CHI have been found in genes regulating insulin secretion from pancreatic beta-cells; recessive inactivating mutations in the ABCC8 and KCNJ11 genes represent the most common events. Despite the advances in understanding the molecular pathogenesis of CHI, specific genetic determinants in about 50 % of the CHI patients remain unknown, suggesting additional locus heterogeneity. In order to search for novel loci contributing to the pathogenesis of CHI, we combined a family-based association study, using the transmission disequilibrium test on 17 CHI patients lacking mutations in ABCC8/KCNJ11, with a whole-exome sequencing analysis performed on 10 probands. This strategy allowed the identification of the potential causative mutations in genes implicated in the regulation of insulin secretion such as transmembrane proteins (CACNA1A, KCNH6, KCNJ10, NOTCH2, RYR3, SCN8A, TRPV3, TRPC5), cytosolic (ACACB, CAMK2D, CDKAL1, GNAS, NOS2, PDE4C, PIK3R3) and mitochondrial enzymes (PC, SLC24A6), and in four genes (CSMD1, SLC37A3, SULF1, TLL1) suggested by TDT family-based association study. Moreover, the exome-sequencing approach resulted to be an efficient diagnostic tool for CHI, allowing the identification of mutations in three causative CHI genes (ABCC8, GLUD1, and HNF1A) in four out of 10 patients. Overall, the present study should be considered as a starting point to design further investigations: our results might indeed contribute to meta-analysis studies, aimed at the identification/confirmation of novel causative or modifier genes.
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No. Sentence Comment
68 We also identified a homozygous ABCC8 variant (p.A390E) in exon 7 within a ROH on chromosome 11 (proband Table 1.
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ABCC8 p.Ala390Glu 23869231:68:49
status: NEW91 Sample ID Gene symbol Chr Position RefSeq ID Amino Acid change PolyPhen/SIFT prediction HI01 HNF1A chr12 121426790 NM_000545 p.A161T* ++/++ KCNH6 chr17 61615518 NM_030779 p.V532F 2/++ HI06 GNAS chr20 57428464 NM_080425 p.E48D +/++ ACACB chr12 109683531 NM_001093 p.N1760S 2/++ NOTCH2 chr1 120464961 NM_024408 p.R1704H +/++ HI18 SLC37A3 chr7 140035229 NM_032295 p.S389L 2/++ CSMD1 chr8 3889535 NM_033225 p.R168W +/++ RYR3 chr15 33938601 NM_001036 p.T1272M +/++ HI26 TRPV3 chr17 3417258 NM_145068 p.L776F ++/++ TRPC5 chrX 111020098 NM_012471 p.G789R 2/++ CAMK2D chr4 114435066 NM_172115 p.R275C ++/++ HI31 PIK3R3 chr1 46521492 NM_003629 p.R306X Nonsense CDKAL1 chr6 21231212 NM_017774 p.S561F 2/++ SCN8A chr12 52163721 NM_014191 p.V1148M 2/++ KCNJ10 chr1 160011280 NM_002241 p.R348H 2/++ HI37 PDE4C chr19 18331081 NM_000923 p.R253C ++/++ HI39 ABCC8 chr11 17428964 NM_000352 p.Q953X* Nonsense ABCC8 chr11 17418595 NM_000352 Splice site NOS2 chr17 26107857 NM_000625 p.R314C ++/++ HI42 ABCC8 chr11 17474673 NM_000352 p.A390E 2/++ SLC24A6 chr12 113737647 NM_024959 p.Y564H ++/++ SULF1 chr8 70501306 NM_015170 p.A222T 2/++ HI43 GLUD1 chr10 88817449 NM_005271 p.S498L* 2/2 TLL1 chr4 166981332 NM_012464 p.G667S ++/2 HI44 CACNA1A chr19 13325090 NM_001127222 p.R1966Q ++/++ PC chr11 66619274 NM_001040716 p.N657Y ++/++ TLL1 chr4 166986893 NM_012464 p.H689P ++/++ *Mutation reported in Human Genome Mutation Database( HGMD).
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ABCC8 p.Ala390Glu 23869231:91:1015
status: NEW