MYO1E mutations and childhood familial focal segmental glomerulosclerosis

Caterina Mele, Paraskevas Iatropoulos, Roberta Donadelli, Andrea Calabria, Ramona Maranta, Paola Cassis, Simona Buelli, Susanna Tomasoni, Rossella Piras, Mira Krendel, Serena Bettoni, Marina Morigi, Massimo Delledonne, Carmine Pecoraro, Isabella Abbate, Maria Rosaria Capobianchi, Friedhelm Hildebrandt, Edgar Otto, Franz Schaefer, Fabio MacciardiFatih Ozaltin, Sevinc Emre, Tulin Ibsirlioglu, Ariela Benigni, Giuseppe Remuzzi, Marina Noris

Research output: Contribution to journalArticlepeer-review


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 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 non-muscle 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 dis-organization 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.

Original languageEnglish
Pages (from-to)295-306
Number of pages12
JournalNew England Journal of Medicine
Issue number4
Publication statusPublished - Jul 28 2011

ASJC Scopus subject areas

  • Medicine(all)


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