Identification of Two Novel Missense Mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) Gene in a Japanese Patient with Pseudoxanthoma Elasticum (PXE)

Noji, Yoshihiro; Inazu, Akihiro; Higashikata, Toshinori; Nohara, Atsushi; Kawashiri, Masa‐aki; Yu, Wenxin; Todo, Yasuhiro; Nozue, Tsuyoshi; Uno, Yusuke; Hifumi, Senshu; Mabuchi, Hiroshi

doi:10.2169/internalmedicine.43.1171

Cited by 22 publications

(15 citation statements)

References 17 publications

(18 reference statements)

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“…To date, more than 150 mutations in ABCC6 have been reported [Bergen et al, 2000;Le Saux et al, 2000;Ringpfeil et al, 2000;Struk et al, 2000;Le Saux et al, 2001;Cai et al, 2001;Meloni et al, 2001;Ringpfeil et al, 2001;Le Saux et al, 2002;Hu et al, 2003b;Chassaing et al, 2004;Gheduzzi et al, 2004;Noji et al, 2004;Chassaing et al, 2005;Hendig et al, 2005;Katona et al, 2005;Miksch et al, 2005;Schulz et al 2006;Kiéc-Wilk et al, 2007]. Most mutations are located at the 3' end of the gene between exons 24 and 30.…”

Section: Introductionmentioning

confidence: 99%

Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart

et al. 2007

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Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder characterized by ocular, cutaneous and cardiovascular manifestations. It is caused by mutations in the ABCC6 gene (chr. 16p13.1), encoding a transmembrane transporter protein, the substrate and biological function of which are currently unknown. A comprehensive clinical and molecular study of 38 Belgian PXE probands and 21 relatives (4 affected and 17 carriers) was performed. An extensive clinical evaluation protocol was implemented with serial fundus, skin and cardiovascular evaluation. We report on 14 novel mutations in the ABCC6 gene. We observed extensive variability in severity of both cutaneous and ocular lesions. The type of skin lesion however usually remained identical throughout the evolution of the disorder, while ophthalmological progression was mainly due to functional decline. Peripheral artery disease (53%) and stroke (15%) were significantly more prevalent than in the general population (10-30% and 0.3-0.5% respectively). Interestingly, we also observed a relatively high incidence of subclinical peripheral artery disease (41%) in our carrier population. We highlight the significance of peripheral artery disease and stroke in PXE patients as well as the subclinical manifestations in carriers. Through follow-up data we gained insight into the natural history of PXE. We propose a cost- and time-efficient two-step method of ABCC6 analysis which can be used in different populations. Additionally, we created a diagnostic flowchart and attempted to define the role of molecular analysis of ABCC6 in the work-up of a PXE patient.

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Section: Introductionmentioning

confidence: 99%

Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart

et al. 2007

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“…PXE is a rare heritable disorder characterized by progressive dermal, ocular and cardiovascular abnormalities that arise through connective tissue alterations and mineralization of elastic fibers [9][10][11][12], which suggested that the lack of ABCC6 function relates to either elastic fibers maintenance or deposition. To date, more than 100 mutations have been characterized in PXE patients [13][14][15][16][17][18]. Most nucleotide variants cluster in specific regions of ABCC6, notably the ATP-binding domains, suggesting that the PXE result lack of transport activity [19].…”

Section: Introductionmentioning

confidence: 99%

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Douet

VanWart

Heller

et al. 2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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SUMMARYMutations in an ABC transporter gene called ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare heritable disease characterized by elastic fiber calcification in skin, ocular and vascular tissues. The presumed function of this ABC transporter is to export metabolites from polarized cells. However, the endogenous substrate(s) are unknown and the exact relationship with elastic fibers is unclear. As ABCC6 is expressed at high level only in liver and kidneys, tissues seemingly unrelated to the PXE phenotype, we explored the transcriptional regulation of the murine Abcc6 gene to define transcriptional regulation conferring tissue specificity and to gather clues on its possible biological function. We cloned 2.9 kb of the mAbcc6 5′-flanking region and several deletion constructs linked to a luciferase reporter gene. We delineated a proximal promoter and a liver-specific enhancer region. We also demonstrated that the proximal region is a TATA-less promoter requiring an intact CCAATbox and Sp1 binding for its basal activity. By using reporter assays and chromatin immunoprecipitations, we showed that HNF4α and surprinsingly, NF-E2, enhanced the mAbcc6 promoter activity. The involvement of both HNF4α and NF-E2 in the mAbcc6 gene regulation suggests that Abcc6 might be involved in a detoxification processes related to hemoglobin or heme.

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“…To date, a total of 122 causative ABCC6 mutations has been identified in PXE patients of different origins (Le Saux et al, 2001;Hu et al, 2003;Gheduzzi et al, 2004;Götting et al, 2004;Noji et al, 2004;Chassaing et al, 2005;Hendig et al, 2005;Katona et al, 2005;Miksch et al, 2005;Schulz et al, 2005a). These include missense, nonsense and splice site mutations, as well as deletions and insertions.…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

et al. 2006

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Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. In the ABCC6 promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.

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Identification of Two Novel Missense Mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) Gene in a Japanese Patient with Pseudoxanthoma Elasticum (PXE)

Cited by 22 publications

References 17 publications

Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart

Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

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