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Olivier Vanakker - One of the best experts on this subject based on the ideXlab platform.
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GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.
International journal of molecular sciences, 2017Co-Authors: Eva De Vilder, Jens Debacker, Olivier VanakkerAbstract:Gamma-carboxylation, performed by Gamma-Glutamyl Carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.
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efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum
Journal of Investigative Dermatology, 2015Co-Authors: Mohammad Jakir Hosen, Filip Van Nieuwerburgh, Wouter Steyaert, Dieter Deforce, Ludovic Martin, Georges Leftheriotis, Anne De Paepe, Paul Coucke, Olivier VanakkerAbstract: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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Retinitis pigmentosa, cutis laxa, and pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations.
The Journal of investigative dermatology, 2014Co-Authors: Ariana Kariminejad, Bita Bozorgmehr, Abdolhamid Najafi, Atefeh Khoshaeen, Maryam Ghalandari, Hossein Najmabadi, Mohamad Hasan Kariminejad, Olivier Vanakker, Mohammad Jakir Hosen, Fransiska MalfaitAbstract:Gamma-Glutamyl Carboxylase (GGCX) mutations have been reported in patients with a pseudoxanthoma elasticum (PXE)–like phenotype, loose redundant skin, and multiple vitamin K–dependent coagulation factor deficiencies. We report on the clinical findings and molecular results in 13 affected members of two families who had a uniform phenotype consisting of (PXE)-like skin manifestations in the neck and trunk, loose sagging skin of the trunk and upper limbs, and retinitis pigmentosa confirmed by electroretinographies in 10 affected individuals. There were no coagulation abnormalities. Molecular investigations of the ATP-binding cassette subfamily C member 6 did not yield causative mutations. All 13 affected family members were found to be homozygous for the splice-site mutation c.373+3G>T in the GGCX gene. All tested parents were heterozygous for the mutation, and healthy siblings were either heterozygous or had the wild type. We suggest that the present patients represent a hitherto unreported phenotype associated with GGCX mutations. Digenic inheritance has been suggested to explain the variability in phenotype in GGCX mutation carriers. Consequently, the present phenotype may not be explained only by the GGCX mutations only but may be influenced by variants in other genes or epigenetic and environmental factors.
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Efficiency of Exome Sequencing for the Molecular Diagnosis of Pseudoxanthoma Elasticum
'Springer Science and Business Media LLC', 2014Co-Authors: M.j. Hosen, Filip Van Nieuwerburgh, Wouter Steyaert, Dieter Deforce, Ludovic Martin, Georges Leftheriotis, Anne De Paepe, Paul Coucke, Olivier VanakkerAbstract: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.Journal of Investigative Dermatology advance online publication, 30 October 2014; doi:10.1038/jid.2014.421
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pseudoxanthoma elasticum like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity
Journal of Investigative Dermatology, 2007Co-Authors: Olivier Vanakker, Ludovic Martin, Paul Coucke, Dealba Gheduzzi, Bart P Leroy, Bart Loeys, Veronica I Guerci, Dirk Matthys, Sharon F Terry, Ivonne PasqualironchettiAbstract:Data on six patients with a Pseudoxanthoma Elasticum (PXE)-like phenotype, characterized by excessive skin folding (resembling cutis laxa) and a deficiency of the vitamin K-dependent clotting factors (II, VII, IX, and X) are presented. A comparison is made between the clinical, ultrastructural, and molecular findings in these patients and those seen in classic PXE and cutis laxa, respectively. Clinical overlap with PXE is obvious from the skin manifestations of yellowish papules or leathery plaques with dot-like depressions at presentation, angioid streaks and/or ocular peau d'orange, and fragmentation and calcification of elastic fibers in the dermis. Important phenotypic differences with PXE include much more severe skin laxity with spreading toward the trunk and limbs with thick, leathery skin folds rather than confinement to flexural areas, and no decrease in visual acuity. Moreover, detailed electron microscopic analyses revealed that alterations of elastic fibers as well as their mineralization were slightly different from those in classic PXE. Molecular analysis revealed neither causal mutations in the ABCC6 gene (ATP-binding cassette subfamily C member 6), which is responsible for PXE, nor in VKORC1 (vitamin K 2,3 epoxide reductase), known to be involved in vitamin K-dependent factor deficiency. However, the GGCX gene (Gamma-Glutamyl Carboxylase), encoding an enzyme important for γ-carboxylation of gla-proteins, harbored mutations in six out of seven patients analyzed. These findings all support the hypothesis that the disorder indeed represents a separate clinical and genetic entity, the molecular background of which remains to be unraveled.
Mohammad Jakir Hosen - One of the best experts on this subject based on the ideXlab platform.
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efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum
Journal of Investigative Dermatology, 2015Co-Authors: Mohammad Jakir Hosen, Filip Van Nieuwerburgh, Wouter Steyaert, Dieter Deforce, Ludovic Martin, Georges Leftheriotis, Anne De Paepe, Paul Coucke, Olivier VanakkerAbstract: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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Retinitis pigmentosa, cutis laxa, and pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations.
The Journal of investigative dermatology, 2014Co-Authors: Ariana Kariminejad, Bita Bozorgmehr, Abdolhamid Najafi, Atefeh Khoshaeen, Maryam Ghalandari, Hossein Najmabadi, Mohamad Hasan Kariminejad, Olivier Vanakker, Mohammad Jakir Hosen, Fransiska MalfaitAbstract:Gamma-Glutamyl Carboxylase (GGCX) mutations have been reported in patients with a pseudoxanthoma elasticum (PXE)–like phenotype, loose redundant skin, and multiple vitamin K–dependent coagulation factor deficiencies. We report on the clinical findings and molecular results in 13 affected members of two families who had a uniform phenotype consisting of (PXE)-like skin manifestations in the neck and trunk, loose sagging skin of the trunk and upper limbs, and retinitis pigmentosa confirmed by electroretinographies in 10 affected individuals. There were no coagulation abnormalities. Molecular investigations of the ATP-binding cassette subfamily C member 6 did not yield causative mutations. All 13 affected family members were found to be homozygous for the splice-site mutation c.373+3G>T in the GGCX gene. All tested parents were heterozygous for the mutation, and healthy siblings were either heterozygous or had the wild type. We suggest that the present patients represent a hitherto unreported phenotype associated with GGCX mutations. Digenic inheritance has been suggested to explain the variability in phenotype in GGCX mutation carriers. Consequently, the present phenotype may not be explained only by the GGCX mutations only but may be influenced by variants in other genes or epigenetic and environmental factors.
Fransiska Malfait - One of the best experts on this subject based on the ideXlab platform.
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Retinitis pigmentosa, cutis laxa, and pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations.
The Journal of investigative dermatology, 2014Co-Authors: Ariana Kariminejad, Bita Bozorgmehr, Abdolhamid Najafi, Atefeh Khoshaeen, Maryam Ghalandari, Hossein Najmabadi, Mohamad Hasan Kariminejad, Olivier Vanakker, Mohammad Jakir Hosen, Fransiska MalfaitAbstract:Gamma-Glutamyl Carboxylase (GGCX) mutations have been reported in patients with a pseudoxanthoma elasticum (PXE)–like phenotype, loose redundant skin, and multiple vitamin K–dependent coagulation factor deficiencies. We report on the clinical findings and molecular results in 13 affected members of two families who had a uniform phenotype consisting of (PXE)-like skin manifestations in the neck and trunk, loose sagging skin of the trunk and upper limbs, and retinitis pigmentosa confirmed by electroretinographies in 10 affected individuals. There were no coagulation abnormalities. Molecular investigations of the ATP-binding cassette subfamily C member 6 did not yield causative mutations. All 13 affected family members were found to be homozygous for the splice-site mutation c.373+3G>T in the GGCX gene. All tested parents were heterozygous for the mutation, and healthy siblings were either heterozygous or had the wild type. We suggest that the present patients represent a hitherto unreported phenotype associated with GGCX mutations. Digenic inheritance has been suggested to explain the variability in phenotype in GGCX mutation carriers. Consequently, the present phenotype may not be explained only by the GGCX mutations only but may be influenced by variants in other genes or epigenetic and environmental factors.
Yusuke Nakamura - One of the best experts on this subject based on the ideXlab platform.
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High-resolution SNP and haplotype maps of the human Gamma-Glutamyl Carboxylase gene (GGCX) and association study between polymorphisms in GGCX and the warfarin maintenance dose requirement of the Japanese population.
Journal of Human Genetics, 2007Co-Authors: Pei-chieng Cha, Takao Suzuki, Taisei Mushiroda, Atsushi Takahashi, Shigeru Saito, Hideki Shimomura, Naoyuki Kamatani, Yusuke NakamuraAbstract:Gamma-Glutamyl Carboxylase (GGCX) plays an important role in blood coagulation through post-translational carboxylation of vitamin K-dependent blood-clotting proteins. This carboxylation process is impaired in the presence of warfarin, a vitamin K antagonist. Recent studies on GGCX have provided insights into association of polymorphisms in this gene, with inter-individual differences in the required warfarin maintenance dose. In order to provide a useful resource for further elucidating this association, we here report a high-resolution single nucleotide polymorphism (SNP) and haplotype maps of an 18-kb genomic region corresponding to the GGCX locus in the Japanese population. Among 41 SNPs, seven insertion/deletion polymorphisms, and a microsatellite polymorphism that we detected by direct sequencing of the DNAs of 96 Japanese individuals who were treated with warfarin, 32 genetic variations have not been reported. Using genotype information from 12 SNPs and the EM algorithm, we estimated haplotypes for this genomic region. Subsequently, we investigated associations of each of these polymorphisms with the warfarin maintenance-dose requirements of 828 Japanese patients, including the 96 patients that were used for DNA sequencing. We found no significant association between the polymorphisms in GGCX and the dose requirement.
Darrel W. Stafford - One of the best experts on this subject based on the ideXlab platform.
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structural and functional insights into enzymes of the vitamin k cycle
Journal of Thrombosis and Haemostasis, 2016Co-Authors: Jianke Tie, Darrel W. StaffordAbstract:Vitamin K-dependent proteins require carboxylation of certain glutamates for their biological functions. The enzymes involved in the vitamin K-dependent carboxylation include: Gamma-Glutamyl Carboxylase (GGCX), vitamin K epoxide reductase (VKOR) and an as-yet-unidentified vitamin K reductase (VKR). Due to the hydrophobicity of vitamin K, these enzymes are likely to be integral membrane proteins that reside in the endoplasmic reticulum. Therefore, structure-function studies on these enzymes have been challenging, and some of the results are notably controversial. Patients with naturally occurring mutations in these enzymes, who mainly exhibit bleeding disorders or are resistant to oral anticoagulant treatment, provide valuable information for the functional study of the vitamin K cycle enzymes. In this review, we discuss: (i) the discovery of the enzymatic activities and gene identifications of the vitamin K cycle enzymes; (ii) the identification of their functionally important regions and their active site residues; (iii) the membrane topology studies of GGCX and VKOR; and (iv) the controversial issues regarding the structure and function studies of these enzymes, particularly, the membrane topology, the role of the conserved cysteines and the mechanism of active site regeneration of VKOR. We also discuss the possibility that a paralogous protein of VKOR, VKOR-like 1 (VKORL1), is involved in the vitamin K cycle, and the importance of and possible approaches for identifying the unknown VKR. Overall, we describe the accomplishments and the remaining questions in regard to the structure and function studies of the enzymes in the vitamin K cycle.
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transmembrane domain interactions and residue proline 378 are essential for proper structure especially disulfide bond formation in the human vitamin k dependent γ glutamyl Carboxylase
Biochemistry, 2008Co-Authors: Jianke Tie, Darrel W. Stafford, Mei Yan Zheng, Kuang Ling N Hsiao, Lalith Perera, David L StraightAbstract:We used recombinant techniques to create a two-chain form (residues 1-345 and residues 346-758) of the vitamin K-dependent Gamma-Glutamyl Carboxylase, a glycoprotein located in the endoplasmic reticulum containing five transmembrane domains. The two-chain Carboxylase had Carboxylase and epoxidase activities similar to those of one-chain Carboxylase. In addition, it had normal affinity for the propeptide of factor IX. We employed this molecule to investigate formation of the one disulfide bond in Carboxylase, the transmembrane structure of Carboxylase, and the potential interactions among the Carboxylase's transmembrane domains. Our results indicate that the two peptides of the two-chain Carboxylase are joined by a disulfide bond. Proline 378 is important for the structure necessary for disulfide formation. Results with the P378L Carboxylase indicate that noncovalent bonds maintain the two-chain structure even when the disulfide bond is disrupted. As we had previously proposed, the fifth transmembrane domain of Carboxylase is the last and only transmembrane domain in the C-terminal peptide of the two-chain Carboxylase. We show that the noncovalent association between the two chains of Carboxylase involves an interaction between the fifth transmembrane domain and the second transmembrane domain. Results of a homology model of transmembrane domains 2 and 5 suggest that not only do these two domains associate but that transmembrane domain 2 may interact with another transmembrane domain. This latter interaction may be mediated at least in part by a motif of glycine residues in the second transmembrane domain.
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identification of a gene encoding a typical γ carboxyglutamic acid domain in the tunicate halocynthia roretzi
Journal of Thrombosis and Haemostasis, 2003Co-Authors: C P Wang, K Yagi, K W Makabe, Darrel W. StaffordAbstract:Summary. We report the identification of a gene capable of encoding a novel Gla (γ-carboxyglutamic acid) protein from the tunicate Halocynthia roretzi, a primitive member of the phylum Chordata. We call this new hypothetical protein Gla-RTK; it has a Gla domain typical of human vitamin K-dependent coagulation factors, a transmembrane domain, and a receptor tyrosine kinase domain. The receptor tyrosine kinase domain is very similar to the ARK (adhesion-related kinase) family of receptor tyrosine kinases. The ARK family includes Axl, Tyro3, and c-Mer. This gene also encodes a propeptide that binds to the human Gamma-Glutamyl Carboxylase within a range of affinities observed for mammalian propeptides. The cDNA for this putative protein is found distributed throughout the oocyte and embryo but the cDNA is apparently not transcribed except during oogenesis. One of the most interesting aspects of this hypothetical protein is that its Gla domain is highly homologous to the Gla domain of Gas6, a ligand for Axl, while its receptor tyrosine kinase domain is highly homologous to Axl.
