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dc.contributor.authorMele, Caterina
dc.contributor.authorIatropoulos, Paraskevas
dc.contributor.authorDonadelli, Roberta
dc.contributor.authorCalabria, Andrea
dc.contributor.authorMaranta, Ramona
dc.contributor.authorCassis, Paola
dc.contributor.authorBuelli, Simona
dc.contributor.authorTomasoni, Susanna
dc.contributor.authorPiras, Rossella
dc.contributor.authorKrendel, Mira
dc.contributor.authorBettoni, Serena
dc.contributor.authorMorigi, Marina
dc.contributor.authorDelledonne, Massimo
dc.contributor.authorPecoraro, Carmine
dc.contributor.authorAbbate, Isabella
dc.contributor.authorCapobianchi, Maria Rosaria
dc.contributor.authorHildebrandt, Friedhelm
dc.contributor.authorOtto, Edgar
dc.contributor.authorSchaefer, Franz
dc.contributor.authorMacciardi, Fabio
dc.contributor.authorOzaltin, Fatih
dc.contributor.authorEmre, Sevinc
dc.contributor.authorIbsirlioglu, Tulin
dc.contributor.authorBenigni, Ariela
dc.contributor.authorRemuzzi, Giuseppe
dc.contributor.authorNoris, Marina
dc.date.accessioned2019-12-10T10:41:55Z
dc.date.available2019-12-10T10:41:55Z
dc.date.issued2011
dc.identifier.issn0028-4793
dc.identifier.urihttps://doi.org/10.1056/NEJMoa1101273
dc.identifier.urihttp://hdl.handle.net/11655/14204
dc.description.abstractBACKGROUND Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive. METHODS We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis (index family) and sequenced a newly discovered gene in 52 unrelated patients with focal segmental glomerulosclerosis. Immunohistochemical studies were performed on human kidney-biopsy specimens and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. RESULTS We identified two mutations (A159P and Y695X) in MYO1E, which encodes a nonmuscle class I myosin, myosin 1E (Myo1E). The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and of the tail domains of Myo1E. CONCLUSIONS MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and the consequent integrity of the glomerular filtration barrier.
dc.language.isoen
dc.publisherMassachusetts Medical Soc
dc.relation.isversionof10.1056/NEJMoa1101273
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGeneral & Internal Medicine
dc.titleMyo1E Mutations And Childhood Familial Focal Segmental Glomerulosclerosis
dc.typeinfo:eu-repo/semantics/article
dc.relation.journalNew England Journal Of Medicine
dc.contributor.departmentÇocuk Sağlığı ve Hastalıkları
dc.identifier.volume365
dc.identifier.issue4
dc.identifier.startpage295
dc.identifier.endpage306
dc.description.indexWoS


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