Identification and Characterization of a New Autoimmune Protein in Membranous Nephropathy by Immunoscreening of a Renal cDNA Library

Fabrizio, Claudia; Magistroni, Riccardo; Furci, Luciana; Lupo, Valentina; Ligabue, Giulia; Granito, M.; Leonelli, Marco; Albertazzi, A; Cappelli, Gianni

doi:10.1371/journal.pone.0048845

Cited by 15 publications

(11 citation statements)

References 25 publications

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“…(42) Indeed, Sc65 is expressed in the kidney and recent work has linked Sc65 auto-immune antibodies with idiopathic human membranous nephropathy. (43) In conclusion, Sc65 is a novel ER-resident protein and not a nuclear/nucleolar antigen in somatic cells. Inactivation of the Sc65 gene in the mouse causes a low bone mass phenotype affecting both trabecular and cortical compartments; this is mediated by increased bone resorption that progresses with age.…”

Section: Discussionmentioning

confidence: 87%

“…Although this confirms a nonoverlapping role for Sc65 with the function of Crtap, it does not exclude the possibility that Sc65 interacts with either P3h2 or P3h3 and may be involved in the hydroxylation of other prolyl residues, perhaps of type IV collagen . Indeed, Sc65 is expressed in the kidney and recent work has linked Sc65 auto‐immune antibodies with idiopathic human membranous nephropathy …”

Section: Discussionmentioning

confidence: 87%

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Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Gruenwald

Castagnola

Besio

et al. 2013

Journal of Bone and Mineral Research

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Members of the Leprecan family of proteins include enzymes, prolyl 3-hydroxylase 1 (P3h1), P3h2 and P3h3, and non-enzymatic proteins, Crtap and Sc65. Mutations in CRTAP and LEPRE1 (encoding P3H1) have been associated with human disease such as recessive osteogenesis imperfecta, however, the function of Sc65 which is closely related and highly homologous to Crtap is unknown. Sc65 has been described as a synaptonemal complex protein, a nucleolar protein, and a cytoplasmic adapter protein. In light of its high sequence similarity with Crtap, an endoplasmic reticulum (ER)-associated protein, and the importance of post-translational modifications such as collagen prolyl 3-hydroxylation in bone metabolism, we hypothesized that Sc65 was an ER-resident protein that would have an important role in bone homeostasis. In this study, we demonstrate that Sc65 is a previously unrecognized ER protein, and that it does not localize in the nucleus of somatic cells. Moreover, Sc65 is expressed and functional during skeletal development since loss of Sc65 results in a progressive osteopenia that affects both trabecular and cortical bone. Bone loss is due to increased bone resorption mediated by a non-cell autonomous effect on osteoclasts. Therefore, Sc65, like its related family member Crtap, is an important modulator of bone homeostasis, acting as a negative regulator of osteoclastogenesis.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Gruenwald

Castagnola

Besio

et al. 2013

Journal of Bone and Mineral Research

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“…These different proteins have likely evolved unique but complimentary functions affecting a wide-range of organ systems. For example, a single point mutation in P3H2 has been implicated in high myopia in humans (35), and a recent study has cited Sc65 as an autoimmune target in membranous nephropathy (36). …”

Section: Prolyl 3-hydroxylase Familymentioning

confidence: 99%

Collagen prolyl 3-hydroxylation: a major role for a minor post-translational modification?

Hudson

Eyre

2013

Connective Tissue Research

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Prolyl 3-hydroxylation is a rare but conserved post-translational modification in many collagen types and, when defective, may be linked to a number of human diseases with musculoskeletal and potentially ocular and renal pathologies. Prolyl 3-hydroxylase-1 (P3H1), the enzyme responsible for converting proline to 3-hydroxyproline (3Hyp) in type I collagen, requires the coenzyme CRTAP for activity. Mass spectrometric analysis showed that the Crtap−/− mouse was missing 3-hydroxyproline in type I collagen α-chains. This finding led to the discovery mutations in genes encoding the P3H1 complex as a cause of recessively inherited osteogenesis imperfecta (brittle bone disease). Since then, many additional 3Hyp sites have been identified in various collagen types and classified based on observed substrate and tissue specificity. P3H1 is part of a family of gene products that also includes isoenzymes P3H2 and P3H3 as well as CRTAP and Sc65. It is believed these isoenzymes and coenzymes have evolved different collagen substrate site and tissue specificities in their activities. The post-translational fingerprinting of collagens will be essential in understanding the basic role and extent of regulated variations of prolyl 3-hydroxylation in collagen. We believe that prolyl 3-hydroxylation is a functionally significant collagen post-translational modification and can be a cause of disease when absent.

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“…Furthermore, autoantibodies against aldose reductase, mitochondrial superoxide dismutase 2, a-enolase and synaptonemal complex protein 65 have been discovered to be present in serum and glomeruli from patients with IMN (6)(7)(8). Therefore, IMN is considered to be an autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

Bullich

Ballarín

Oliver³

et al. 2014

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ a-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease.Design, settings, participants, & measurements A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed.Results This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. ConclusionThis study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

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Identification and Characterization of a New Autoimmune Protein in Membranous Nephropathy by Immunoscreening of a Renal cDNA Library

Cited by 15 publications

References 25 publications

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Collagen prolyl 3-hydroxylation: a major role for a minor post-translational modification?

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

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