title: Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations.
abstract: The oculocerebrorenal syndrome of Lowe gene (OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions.
  
  
  
  We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D).
  
  
  
  All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study.
  
  
  
  Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood.
authors.affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Chikushi
authors.initials: C
authors.lastname: Suruda
authors.affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Sohsaku
authors.initials: S
authors.lastname: Yamanouchi
authors.affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kimata
authors.affiliation: Division of Nephrology, 2nd Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
authors.forename: Nguyen Thanh
authors.initials: NT
authors.lastname: Huan
authors.affiliation: Diagnostics Research Department, Life Innovation Research Institute, Denka Innovation Center, Denka Co. Ltd., Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Diagnostics Research Department, Life Innovation Research Institute, Denka Innovation Center, Denka Co. Ltd., Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: Division of Nephrology, 2nd Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsukaguchi
authors.affiliation: Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan. kanekok@hirakata.kmu.ac.jp.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D000293:Adolescent; D000375:Aging / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D057973:Dent Disease / Q000235:genetics / Q000652:urine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000032:analysis* / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008970:Molecular Weight; D009154:Mutation; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000652:urine; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011507:Proteinuria / Q000235:genetics / Q000652:urine; D001613:beta 2-Microglobulin / Q000652:urine
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D001613:beta 2-Microglobulin; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human
keywords: Dent disease; Inositol polyphosphate-5-phosphatase; Lowe syndrome; Megalin; OCRL; Tubular proteinuria