MYO1E mutations and childhood familial focal segmental glomerulosclerosis
| Autor: | Serena Bettoni, Ariela Benigni, Paola Cassis, Mira Krendel, Susanna Tomasoni, Giuseppe Remuzzi, Franz Schaefer, Fatih Ozaltin, Fabio Macciardi, Marina Morigi, Marina Noris, Isabella Abbate, Tulin Ibsirlioglu, Carmine Pecoraro, Rossella Piras, Andrea Calabria, Roberta Donadelli, Ramona Maranta, Sevinç Emre, Simona Buelli, Friedhelm Hildebrandt, Paraskevas Iatropoulos, Massimo Delledonne, Caterina Mele, Edgar A. Otto, Maria Rosaria Capobianchi |
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| Přispěvatelé: | Çocuk Sağlığı ve Hastalıkları |
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Pathology focal Segmental Glomerulosclerosis Genetic Linkage Kidney Glomerulus Drug Resistance Mutation Missense Genes Recessive targeted resequencing mutations medicine.disease_cause Podocyte Mice Myosin Type I Focal segmental glomerulosclerosis General & Internal Medicine Internal medicine medicine Animals Humans Age of Onset Child Glucocorticoids Mutation Primary Focal Segmental Glomerulosclerosis business.industry Glomerulosclerosis Focal Segmental Podocytes Glomerular basement membrane Infant General Medicine medicine.disease Pedigree medicine.anatomical_structure Endocrinology Microscopy Fluorescence Child Preschool Glomerular Filtration Barrier Female business Nephrotic syndrome Sequence Alignment Kidney disease Genome-Wide Association Study |
| Zdroj: | The New England journal of medicine. 365(4) |
| ISSN: | 1533-4406 |
| Popis: | A B S T R AC T Background Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to endstage 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. |
| Databáze: | OpenAIRE |
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