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dc.contributor.authorStefanou, Charalambosen
dc.contributor.authorPieri, Myrtanien
dc.contributor.authorSavva, Isavellaen
dc.contributor.authorGeorgiou, Georgios C.en
dc.contributor.authorPierides, Alkis M.en
dc.contributor.authorVoskarides, Konstantinosen
dc.contributor.authorConstantinou-Deltas, Constantinos D.en
dc.creatorStefanou, Charalambosen
dc.creatorPieri, Myrtanien
dc.creatorSavva, Isavellaen
dc.creatorGeorgiou, Georgios C.en
dc.creatorPierides, Alkis M.en
dc.creatorVoskarides, Konstantinosen
dc.creatorConstantinou-Deltas, Constantinos D.en
dc.date.accessioned2019-11-04T12:52:44Z
dc.date.available2019-11-04T12:52:44Z
dc.date.issued2015
dc.identifier.issn2235-3186
dc.identifier.urihttp://gnosis.library.ucy.ac.cy/handle/7/53405
dc.description.abstractBACKGROUND/AIMS: A subset of patients who present with proteinuria and are diagnosed with focal segmental glomerulosclerosis (FSGS) have inherited heterozygous COL4A3/A4 mutations and are also diagnosed with thin basement membrane nephropathy (TBMN-OMIM: 141200). Two studies showed that co-inheritance of NPHS2-p.Arg229Gln, a podocin variant, may increase the risk for proteinuria and renal function decline. METHODS: We hypothesized that additional podocin variants may exert a similar effect. We studied genetically a well-characterized Cypriot TBMN patient cohort by re-sequencing the NPHS2 coding region. We also performed functional studies in cell culture experiments, investigating the interaction of podocin variants with itself and with nephrin. RESULTS: Potentially disease-modifying podocin variants were searched for by analyzing NPHS2 in 35 'severe' TBMN patients. One non-synonymous variant, p.Glu237Gln, was detected. Both variants, p.Arg229Gln and p.Glu237Gln, were tested in a larger cohort of 122 TBMN patients, who were categorized as 'mild' or 'severe' based on the presence of microscopic hematuria alone or combined with chronic renal failure and/or proteinuria. Seven 'severe' patients carried either of the 2 variantsen
dc.description.abstractnone was present in the 'mild' patients (p = 0.05, Pearson χ(2)). The 7 carriers belong in 2 families segregating mutation COL4A3-p.Gly1334Glu. Inheritance of the wild-type (WT) and mutant alleles correlated with the phenotype (combined concordance probability 0.003). Immunofluorescence (IF) experiments after dual co-transfection of WT and mutant podocin suggested altered co-localization of mutant homodimers. IF experiments after co-transfection of WT podocin and nephrin showed normal membrane localization, while both podocin variants interfered with normal trafficking, demonstrating perinuclear staining. Immunoprecipitation experiments showed stronger binding of mutant podocin to WT podocin or nephrin. CONCLUSION: The results support the hypothesis that certain hypomorphic podocin variants may act as adverse genetic modifiers when co-inherited with COL4A3/A4 mutations, thus predisposing to FSGS and severe kidney function decline. 2015 S. Karger AG, Basel.en
dc.sourceNephronen
dc.source.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84979842393&doi=10.1159%2f000432406&partnerID=40&md5=3f7d54ff2931d428fc7b223ad570e5a2
dc.subjecthumanen
dc.subjectHumansen
dc.subjectageden
dc.subjectfemaleen
dc.subjectDisease Progressionen
dc.subjectdisease courseen
dc.subjectmaleen
dc.subjectalleleen
dc.subjectsex differenceen
dc.subjectpathologyen
dc.subjectmiddle ageden
dc.subjectAutoantigensen
dc.subjectcohort analysisen
dc.subjectproteinuriaen
dc.subjectSex Factorsen
dc.subjectgeneticsen
dc.subjectAllelesen
dc.subjectheterozygoteen
dc.subjectCohort Studiesen
dc.subjectcollagen type 4en
dc.subjectMembrane Proteinsen
dc.subjectmembrane proteinen
dc.subjectmutationen
dc.subjectCollagen Type IVen
dc.subjectKidney Failure, Chronicen
dc.subjectpedigreeen
dc.subjectglomerulus basement membraneen
dc.subjectfocal glomerulosclerosisen
dc.subjectGlomerular Basement Membraneen
dc.subjectautoantigenen
dc.subjectGlomerulosclerosis, Focal Segmentalen
dc.subjectsignal peptideen
dc.subjecttype IV collagen alpha3 chainen
dc.subjectIntracellular Signaling Peptides and Proteinsen
dc.subjectpodocinen
dc.titleCo-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failureen
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1159/000432406
dc.description.volume130
dc.description.startingpage200
dc.description.endingpage212
dc.author.facultyΣχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences
dc.author.departmentΤμήμα Βιολογικών Επιστημών / Department of Biological Sciences
dc.type.uhtypeArticleen
dc.description.notes<p>Cited By :3</p>en
dc.source.abbreviationNephronen
dc.contributor.orcidConstantinou-Deltas, Constantinos D. [0000-0001-5549-9169]
dc.gnosis.orcid0000-0001-5549-9169


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