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ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones.

Plomp AS, Florijn RJ, Ten Brink J, Castle B, Kingston H, Martín-Santiago A, Gorgels TG, de Jong PT, Bergen AA - Mol. Vis. (2008)

Bottom Line: Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients.Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE.In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Ophthalmogenetics, Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

ABSTRACT

Purpose: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissue, affecting the retina, the skin, and the cardiovascular system. PXE is caused by mutations in ABCC6. Up to now, the literature reports that there are 180 different ABCC6 mutations in PXE. The purpose of this paper is to report eight novel mutations in ABCC6 and to update the spectrum and frequency of ABCC6 mutations in PXE patients.

Methods: Eye, skin, and DNA examinations were performed using standard methodologies. We newly investigated the gene in 90 probands by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We examined a total of 166 probands.

Results: Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients. Currently, our mutation detection score is at least one ABCC6 mutation in 87% of patients with a clinical diagnosis of PXE.

Conclusions: Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE. In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.

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Related in: MedlinePlus

Schematic representation of the MRP6 protein. The protein contains 17 membrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The percentages in the figure show how the mutations in our population are distributed over the different domains of the protein. The eighth cytoplasmatic loop is the most frequently mutated domain, followed by the region between the last transmembrane-spanning domain and NBF2 and by NBF2 itself. Del=deletion. In addition, 1% of the population had a deletion of the whole gene.
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f1: Schematic representation of the MRP6 protein. The protein contains 17 membrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The percentages in the figure show how the mutations in our population are distributed over the different domains of the protein. The eighth cytoplasmatic loop is the most frequently mutated domain, followed by the region between the last transmembrane-spanning domain and NBF2 and by NBF2 itself. Del=deletion. In addition, 1% of the population had a deletion of the whole gene.

Mentions: ABCC6 belongs to the ATP-binding cassette (ABC) gene sub-family C [10,11]. ABCC6 has 31 exons spanning about 73 kb genomic DNA. The mRNA is approximately 6 kb with an open reading frame (ORF) of 4.5 kb. The ABCC6 protein consists of 1,503 amino acids and contains 17 transmembrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The NBFs consist of Walker A and B domains and a C motif critical for active ATP dependent transport across the cell membrane [1,12]. The putative ABCC6 protein structure is presented in Figure 1. Two ABCC6 pseudogenes, homologous to, respectively, the first four and nine exons of ABCC6, have been identified [13,14], complicating the mutational analysis of the gene [15].


ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones.

Plomp AS, Florijn RJ, Ten Brink J, Castle B, Kingston H, Martín-Santiago A, Gorgels TG, de Jong PT, Bergen AA - Mol. Vis. (2008)

Schematic representation of the MRP6 protein. The protein contains 17 membrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The percentages in the figure show how the mutations in our population are distributed over the different domains of the protein. The eighth cytoplasmatic loop is the most frequently mutated domain, followed by the region between the last transmembrane-spanning domain and NBF2 and by NBF2 itself. Del=deletion. In addition, 1% of the population had a deletion of the whole gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254972&req=5

f1: Schematic representation of the MRP6 protein. The protein contains 17 membrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The percentages in the figure show how the mutations in our population are distributed over the different domains of the protein. The eighth cytoplasmatic loop is the most frequently mutated domain, followed by the region between the last transmembrane-spanning domain and NBF2 and by NBF2 itself. Del=deletion. In addition, 1% of the population had a deletion of the whole gene.
Mentions: ABCC6 belongs to the ATP-binding cassette (ABC) gene sub-family C [10,11]. ABCC6 has 31 exons spanning about 73 kb genomic DNA. The mRNA is approximately 6 kb with an open reading frame (ORF) of 4.5 kb. The ABCC6 protein consists of 1,503 amino acids and contains 17 transmembrane-spanning domains and two intracellular nucleotide binding folds (NBFs). The NBFs consist of Walker A and B domains and a C motif critical for active ATP dependent transport across the cell membrane [1,12]. The putative ABCC6 protein structure is presented in Figure 1. Two ABCC6 pseudogenes, homologous to, respectively, the first four and nine exons of ABCC6, have been identified [13,14], complicating the mutational analysis of the gene [15].

Bottom Line: Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients.Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE.In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Ophthalmogenetics, Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

ABSTRACT

Purpose: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissue, affecting the retina, the skin, and the cardiovascular system. PXE is caused by mutations in ABCC6. Up to now, the literature reports that there are 180 different ABCC6 mutations in PXE. The purpose of this paper is to report eight novel mutations in ABCC6 and to update the spectrum and frequency of ABCC6 mutations in PXE patients.

Methods: Eye, skin, and DNA examinations were performed using standard methodologies. We newly investigated the gene in 90 probands by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We examined a total of 166 probands.

Results: Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients. Currently, our mutation detection score is at least one ABCC6 mutation in 87% of patients with a clinical diagnosis of PXE.

Conclusions: Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE. In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.

Show MeSH
Related in: MedlinePlus