title: In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.
abstract: BACKGROUND
  The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear.
  
  
  METHODS
  A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene.
  
  
  CONCLUSIONS
  The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.
authors.affiliation: Division of Pediatrics, CHC Liège, Liège, Belgium.
authors.forename: Angélique
authors.initials: A
authors.lastname: Dachy
authors.forename: François
authors.initials: F
authors.lastname: Paquot
authors.forename: Guillaume
authors.initials: G
authors.lastname: Debray
authors.forename: Christophe
authors.initials: C
authors.lastname: Bovy
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.forename: Laure
authors.initials: L
authors.lastname: Collard
authors.forename: François
authors.initials: F
authors.lastname: Jouret
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D001706:Biopsy; D024403:Carbonic Anhydrase III / Q000652:urine; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004705:Endocytosis; D005260:Female; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D065630:Hernias, Diaphragmatic, Congenital / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008854:Microscopy, Electron; D009154:Mutation; D009216:Myopia / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D011507:Proteinuria / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D011956:Receptors, Cell Surface / Q000378:metabolism; D015499:Renal Tubular Transport, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000652:urine
chemical_list: C000597357:LRP2 protein, human; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor; D024403:Carbonic Anhydrase III
references.citation: Nephron Physiol. 2005;99(3):p69-73
references.pmid: 15637424
references.citation: Kidney Int. 2004 Jan;65(1):198-208
references.pmid: 14675051
references.citation: Kidney Int. 2008 Jul;74(1):52-61
references.pmid: 18322545
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14 ):8472-7
references.pmid: 12815097
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18810-5
references.pmid: 17121993
references.citation: Glia. 2012 May;60(6):851-66
references.pmid: 22354480
references.citation: Physiology (Bethesda). 2012 Aug;27(4):223-36
references.pmid: 22875453
references.citation: Am J Physiol Renal Physiol. 2014 Jan;306(2):F147-54
references.pmid: 24197071
references.citation: Am J Pathol. 1999 Oct;155(4):1361-70
references.pmid: 10514418
references.citation: Development. 2005 Jan;132(2):405-14
references.pmid: 15623804
references.citation: Nephrol Dial Transplant. 2013 Mar;28(3):585-91
references.pmid: 23048173
references.citation: Pflugers Arch. 2009 Apr;457(6):1227-36
references.pmid: 18839205
references.citation: Birth Defects Res A Clin Mol Teratol. 2009 Jan;85(1):76-81
references.pmid: 19089858
references.citation: Nat Genet. 2007 Aug;39(8):957-9
references.pmid: 17632512
references.citation: Cell Tissue Res. 2014 Oct;358(1):99-107
references.pmid: 24980834