ABCC6 p.Gly1501Ser
| LOVD-ABCC6: |
p.Gly1501Ser
D
|
| Predicted by SNAP2: | A: D (59%), C: D (59%), D: D (71%), E: D (71%), F: D (71%), H: D (59%), I: D (71%), K: D (66%), L: D (71%), M: D (66%), N: N (53%), P: D (75%), Q: D (53%), R: D (71%), S: D (53%), T: D (66%), V: D (66%), W: D (75%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Mutation detection in the ABCC6 gene and genotype-... J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6. Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, Fratta S, Marais AS, Hariri S, Coucke PJ, Ramsay M, Viljoen D, Terry PF, De Paepe A, Uitto J, Bercovitch LG
Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6., [PMID:17617515]
Abstract [show]
BACKGROUND: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). OBJECTIVE: To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. METHODS: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. RESULTS: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. CONCLUSIONS: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
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No. Sentence Comment
277 Finally, there is the possibility that mutations in genes other than ABCC6 can Nucleotide change*À Predicted consequenceÀ Frequency (alleles) Exon-intron location Domain affected` Mutant alleles (%) References1 c.4041gRc p.Q1347H 1 28 NBF2 0.3 25 c.4104delC FS 1 29 0.3 25 c.4192cRt p.R1398X 2 29 0.6 25 c.4335delG FS 1 30 0.3 c.4441gRa p.G1481S 1 31 NBF2 0.3 c.4501gRa p.G1501S 1 31 NBF2 0.3 Ex23_29del p.A999_S1403del 57 23-29 18.0 15, 18, 21, 25, 27, 28, 31, 32, 37, 44, 45 FS, frameshift; IC, intracellular domain; IVS, intron; NBF, nucleotide binding fold; SJ, splice junction; TM, transmembrane domain.
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ABCC6 p.Gly1501Ser 17617515:277:382
status: NEW[hide] Regulation of ABCC6 trafficking and stability by a... PLoS One. 2014 May 19;9(5):e97360. doi: 10.1371/journal.pone.0097360. eCollection 2014. Xue P, Crum CM, Thibodeau PH
Regulation of ABCC6 trafficking and stability by a conserved C-terminal PDZ-like sequence.
PLoS One. 2014 May 19;9(5):e97360. doi: 10.1371/journal.pone.0097360. eCollection 2014., [PMID:24840500]
Abstract [show]
Mutations in the ABCC6 ABC-transporter are causative of pseudoxanthoma elasticum (PXE). The loss of functional ABCC6 protein in the basolateral membrane of the kidney and liver is putatively associated with altered secretion of a circulatory factor. As a result, systemic changes in elastic tissues are caused by progressive mineralization and degradation of elastic fibers. Premature arteriosclerosis, loss of skin and vascular tone, and a progressive loss of vision result from this ectopic mineralization. However, the identity of the circulatory factor and the specific role of ABCC6 in disease pathophysiology are not known. Though recessive loss-of-function alleles are associated with alterations in ABCC6 expression and function, the molecular pathologies associated with the majority of PXE-causing mutations are also not known. Sequence analysis of orthologous ABCC6 proteins indicates the C-terminal sequences are highly conserved and share high similarity to the PDZ sequences found in other ABCC subfamily members. Genetic testing of PXE patients suggests that at least one disease-causing mutation is located in a PDZ-like sequence at the extreme C-terminus of the ABCC6 protein. To evaluate the role of this C-terminal sequence in the biosynthesis and trafficking of ABCC6, a series of mutations were utilized to probe changes in ABCC6 biosynthesis, membrane stability and turnover. Removal of this PDZ-like sequence resulted in decreased steady-state ABCC6 levels, decreased cell surface expression and stability, and mislocalization of the ABCC6 protein in polarized cells. These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein.
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No. Sentence Comment
189 The PXE-associate G1501S site is highlighted in red.
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ABCC6 p.Gly1501Ser 24840500:189:18
status: NEW345 However, a single PXE patient in which the G1501S mutation was found was reported to show phenotypic abnormalities in the eye (bleeding/scarring) and mild presentation in the skin (papules/bumps), but presented without apparent GI, vascular or cardiac symptoms.
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ABCC6 p.Gly1501Ser 24840500:345:43
status: NEW