ABCC6 p.Arg807Gln
| LOVD-ABCC6: |
p.Arg807Trp
D
p.Arg807Gln D |
| 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%), Q: 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: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Pseudoxanthoma elasticum: a clinical, pathophysiol... J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A
Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.
J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13., [PMID:15894595]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.
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No. Sentence Comment
378 Interestingly, among the 49 different missense mutations in ABCC6 (42 previously published and seven new ones in the present study), the majority (43) replace critical amino acids in intracellular domains (seven and 19 mutations are located in I1424T R1459C 4220insAGAA 4318delA G1354R D1361N K1394N E1400K R1298X 410delC 418delG 3775delT R1275X R1221C D1238H W1223X Q1237X IVS26-1G→A R1114C R1114H R1114P S1121W M1127T T1130M R1138P R1138Q R1138W R1141X R1164X R765Q A766D Y768X A781V 2322delC IVS19-2delAG T364R R391G Q378X Q363_R373del 938_939insT 960delC IVS8+2delTG G199X Y227X 179_195del 179_187del G226R V74del Q749X IVS17-12delTT IVS14-5T→G IVS13-29T→A R600G V1298F G1299S T1301I G1302R A1303P S1307P R1314Q R1314W G1321S L1335P R1339C P1346S Q1347H R1030X F1048del R807Q V810M A820P 254delG L673P 1944_1966del 1995delG R518Q R518X K502M A455P G992R IVS21+1G→T G1203DF568SN411K C440G IVS25-3C→A 3544dupC Ex23_29del 30 Ex15del ABCC6del 252015105 Figure 10 Position of the mutations in the ABCC6 gene.
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ABCC6 p.Arg807Gln 15894595:378:795
status: NEW[hide] Molecular genetics of pseudoxanthoma elasticum: ty... Hum Mutat. 2005 Sep;26(3):235-48. Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, Ramesar RK, Lebwohl M, Hohl D, Neldner KH, Lindpaintner K, Richards RI, Struk B
Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.
Hum Mutat. 2005 Sep;26(3):235-48., [PMID:16086317]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.
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288 While the correct folding of ABCC7 has been proposed to depend on the integrity of the NBF1 region and its interaction with surrounding domains, particularly the NBF2 domain [Dalemans et al., 1991; Pollet et al., 2000], a similar loss-of-function mechanism can be proposed for ABCC6 mutations (L677P and R760W) within or around NBF1 (R807W and R807Q).
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ABCC6 p.Arg807Gln 16086317:288:344
status: NEW[hide] Parameters of oxidative stress are present in the ... Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10. Garcia-Fernandez MI, Gheduzzi D, Boraldi F, Paolinelli CD, Sanchez P, Valdivielso P, Morilla MJ, Quaglino D, Guerra D, Casolari S, Bercovitch L, Pasquali-Ronchetti I
Parameters of oxidative stress are present in the circulation of PXE patients.
Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10., [PMID:18513494]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by calcification of elastic fibres leading to dermatological and vascular alterations associated to premature aged features and to life threatening clinical manifestations. The severity of the disease is independent from the type of mutation in the ABCC6 gene, and it has been suggested that local and/or systemic factors may contribute to the occurrence of clinical phenotype. The redox balance in the circulation of 27 PXE patients and of 50 healthy subjects of comparable age was evaluated by measuring the advanced oxidation protein products (AOPP), the lipid peroxidation derivatives (LOOH), the circulating total antioxidant status (TAS), the thiol content and the extracellular superoxide dismutase activity (EC-SOD). Patients were diagnosed by clinical, ultrastructural and molecular findings. Compared to control subjects, PXE patients exhibited significantly lower antioxidant potential, namely circulating TAS and free thiol groups, and higher levels of parameters of oxidative damage, as LOOH and of AOPP, and of circulating EC-SOD activity. Interestingly, the ratio between oxidant and antioxidant parameters was significantly altered in PXE patients and related to various score indices. This study demonstrates, for the first time, that several parameters of oxidative stress are modified in the blood of PXE patients and that the redox balance is significantly altered compared to control subjects of comparable age. Therefore, in PXE patients the circulating impaired redox balance may contribute to the occurrence of several clinical manifestations in PXE patients, and/or to the severity of disease, thus opening new perspectives for their management.
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74 Table 1 Clinical data of patients Patients' gender/age Clinical scores Mutations Allele 1 Allele 2 M/10 S2E2 c.3413GNA (p.R1138Q) c.3413GNA (p.R1138Q) F/16 S1 c.1171ANG (p.R391G) c.1552CNT (p.R518X) F/18 S3E2V2 c.1484TNA (p.L495H) c.1484TNA (p.L495H) F/21 S2E2 c.2420GNA (p.R807Q) ND F/21 S2E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/24 S2E2 c.1799GNA (p.R600H) c.2420GNA (p.R807Q) F/27 S3E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/30 S2E2G1 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) F/30 S2E3 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) M/30 S2E1 c.3421CNT (p.R1141X) c.3735GNA F/32 S2 c.3421CNT (p.R1141X) c.3735GNA F/33 S3E2 c.1987GNA (p.G663S) ND F/33 S3E3 c.1609_1609delG (p.V537fsX26) c.1763_1769del ins56 F/36 S3E2V3 c.3421CNT (p.R1141X) ND F/36 S3E3V2G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) M/39 S1E2V2 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) M/42 S1E3V2G1 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) F/43 S3E3 c.1552CNT (p.R518X) c.1552CNT (p.R518X) F/44 S3E2 c.3341GNA (p.R1114H) c.3542GNA (p.G1181D) F/45 S3E3V2C1G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) F/48 S2E2V2 c.1553GNA (p.R518Q) ND M/51 S1E3 c.3662GNA (p.R1221H) ND F/52 S3E3V2 c.3088CNT (p.R1030X) c.3088CNT (p.R1030X) M/54 S1E2G1 c.1799GNA (p.R600H) c.3941GNA (p.R1314Q) F/56 S3E3V2 c.3662GNA (p.R1221H) ND F/60 S2E3V2C1G1 c.951CNA (p.S317R) c.3421CNT (p.R1141X) F/62 S2E3 c.1552CNT (p.R518X) c.3421CNT (p.R1141X) Scores describe the severity of clinical manifestations.
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ABCC6 p.Arg807Gln 18513494:74:274
status: NEWX
ABCC6 p.Arg807Gln 18513494:74:388
status: NEW