title: Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration.
abstract: BACKGROUND
  The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria. In this study, we examined the role of megalin for tubular protein reabsorption in humans through analysis of proximal tubular function in megalin-deficient patients.
  
  
  METHODS
  Direct sequencing of the megalin-encoding gene (LRP2) was performed in a family in which three children presented with classical DB/FOAR manifestations. Renal consequences of megalin deficiency were investigated through immunohistochemical analyses of renal biopsy material and immunoblotting of urine samples.
  
  
  RESULTS
  In the patients, a characteristic urinary protein profile with increased urinary excretion of vitamin D-binding protein, retinol-binding protein and albumin was associated with absence of, or reduced, proximal tubular endocytic uptake as shown by renal immunohistochemistry. In the absence of tubular uptake, urinary albumin excretion was in the micro-albuminuric range suggesting that limited amounts of albumin are filtered in human glomeruli.
  
  
  CONCLUSIONS
  This study demonstrated that megalin plays an essential role for human proximal tubular protein reabsorption and suggests that only limited amounts of albumin is normally filtered in the human glomeruli. Finally, we propose that the characteristic urinary protein profile of DB/FOAR patients may be utilized as a diagnostic marker of megalin dysfunction.
authors.affiliation: Department of Biomedicine, Universityof Aarhus, Aarhus, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Storm
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjærg
authors.forename: Carina
authors.initials: C
authors.lastname: Frykholm
authors.forename: Henrik
authors.initials: H
authors.lastname: Birn
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Verroust
authors.forename: Tryggve
authors.initials: T
authors.lastname: Nevéus
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sundelin
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.forename: Gerd
authors.initials: G
authors.lastname: Holmström
authors.forename: Katharina
authors.initials: K
authors.lastname: Ericson
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.forename: Rikke
authors.initials: R
authors.lastname: Nielsen
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000418:Albumins / Q000378:metabolism*; D002675:Child, Preschool; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009216:Myopia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015499:Renal Tubular Transport, Inborn Errors
chemical_list: D000418:Albumins; D026561:Low Density Lipoprotein Receptor-Related Protein-2