ABCC6 p.Gln1406Lys
| ClinVar: |
c.4216C>A
,
p.Gln1406Lys
D
, Pathogenic
|
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] An unusual severe vascular case of pseudoxanthoma ... Am J Med Genet A. 2010 Jan;152A(1):118-23. Le Boulanger G, Labreze C, Croue A, Schurgers LJ, Chassaing N, Wittkampf T, Rutsch F, Martin L
An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy.
Am J Med Genet A. 2010 Jan;152A(1):118-23., [PMID:20034067]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease affecting tissues rich in elastic fibers such as the skin, retina, and cardiovascular system. Mutations in the ABCC6 gene are known to be causative in most patients. Generalized arterial calcification of infancy (GACI) is characterized by extensive hydroxyapatite deposits in the internal elastic laminae in large and medium-sized arteries, leading to arterial stenoses and early and severe myocardial ischemia. GACI has been found to be primarily caused by mutations in the ENPP1 gene. We report two brothers born to unrelated parents. The elder developed uncomplicated PXE in adolescence and harbored mutations in the ABCC6 gene. The younger child died of a condition strikingly reminiscent of GACI at 15 months of age. This case of GACI was independent of mutations in the ENPP1 gene but was probably related to ABCC6 mutations. We demonstrate that matrix Gla protein and fetuin-A, involved in PXE, are also expressed in this case of GACI. These proteins could act as local and systemic inhibitors to limit the extension of mineralization. This report emphasizes concurrently that ABCC6 may be a relevant candidate gene in some cases of GACI with no mutations in the ENPP1 gene, and that GACI may be an atypical and severe end of the vascular phenotype spectrum of PXE.
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No. Sentence Comment
101 Cervicalyellowishpapulescharacteristicofpseudoxanthoma elasticum in the elder brother aged 28. p.Arg765Gln and p.Gln1406Lys, demonstrating PXE.
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ABCC6 p.Gln1406Lys 20034067:101:114
status: NEW[hide] Efficiency of exome sequencing for the molecular d... J Invest Dermatol. 2015 Apr;135(4):992-8. doi: 10.1038/jid.2014.421. Epub 2014 Sep 29. Hosen MJ, Van Nieuwerburgh F, Steyaert W, Deforce D, Martin L, Leftheriotis G, De Paepe A, Coucke PJ, Vanakker OM
Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.
J Invest Dermatol. 2015 Apr;135(4):992-8. doi: 10.1038/jid.2014.421. Epub 2014 Sep 29., [PMID:25264593]
Abstract [show]
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exomes with insufficient reads (20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.
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89 List of mutations found by WES and SS Gene Nucleotide change Protein change Patient ID Hom/Het WES SS Known/PUR Reference ABCC6 c.C118T p.(P40S) P10 Het O O PUR ABCC6 c.998 &#fe; 2 998 &#fe; 3del TG P8 Het O O PUR ABCC6 c.T1484A p.(L495H) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G1553A p.(R518Q) P11 Hom O O Known Uitto et al., 2001 ABCC6 c.G1553A p.(R518Q) P12, P13, P14 Het O O Known Uitto et al., 2001 ABCC6 c.G2263A p.(G755R) P11 Het O O Known Pfendner et al., 2007 ABCC6 c.G2294A p.(R765Q) P3 Het O O Known Le Saux et al., 2001 ABCC6 del2860_2865 P12, P13,14 Het O O PUR ABCC6 c.T2911C p.(W971R) P11 Het O O PUR ABCC6 Ex23_24del P2 Hom O O Known Ringpfeil et al., 2001 ABCC6 c.T3032C p.(L1011P) P9 Hom O O PUR ABCC6 c.C3190T p.(A1064T) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G3413A p.(R1138Q) P11 Het O O Known Le Saux O, 2011 ABCC6 c.C3421T p.(R1141X) P4 Hom O O Known Bergen et al., 2000 ABCC6 c.C3421T p.(R1141X) P52 , P8, P162 Het O O Known Bergen et al., 2000 ABCC6 c.C3490T p.(R1164X) P6, P15 Hom O O Known Struk et al., 2000 ABCC6 c.G4198A p.(E1400K) P10 Het O O Known Chassaing et al., 2004 ABCC6 c.C4216A p.(Q1406K) P3 Het O O PUR GGCX c.C1321T p.(R441C) P7 Het O O PUR Het, heterozygous; Hom, homozygous; PUR, previously unreported; SS, Sanger sequencing; WES, whole-exome sequencing.
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ABCC6 p.Gln1406Lys 25264593:89:1133
status: NEW