title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
abstract: 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 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò Ranica, Bergamo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mele
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Iatropoulos
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Calabria
authors.forename: Ramona
authors.initials: R
authors.lastname: Maranta
authors.forename: Paola
authors.initials: P
authors.lastname: Cassis
authors.forename: Simona
authors.initials: S
authors.lastname: Buelli
authors.forename: Susanna
authors.initials: S
authors.lastname: Tomasoni
authors.forename: Rossella
authors.initials: R
authors.lastname: Piras
authors.forename: Mira
authors.initials: M
authors.lastname: Krendel
authors.forename: Serena
authors.initials: S
authors.lastname: Bettoni
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Massimo
authors.initials: M
authors.lastname: Delledonne
authors.forename: Carmine
authors.initials: C
authors.lastname: Pecoraro
authors.forename: Isabella
authors.initials: I
authors.lastname: Abbate
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Capobianchi
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Edgar
authors.initials: E
authors.lastname: Otto
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.forename: Sevinc
authors.initials: S
authors.lastname: Emre
authors.forename: Tulin
authors.initials: T
authors.lastname: Ibsirlioglu
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
mesh_terms: D017668:Age of Onset; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D007678:Kidney Glomerulus / Q000098:blood supply / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D020125:Mutation, Missense; D024461:Myosin Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D016415:Sequence Alignment
chemical_list: D005938:Glucocorticoids; C511011:MYO1E protein, human; D024461:Myosin Type I