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.

CLINICAL CASE:

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: Angélique Dachy, François Paquot, Guillaume Debray, Christophe Bovy, Erik I Christensen, Laure Collard, François Jouret
• Journal: Pediatric nephrology (Berlin, Germany) (Pediatr Nephrol) Vol. 30 Issue 6 Pg. 1027-31 (Jun 2015) ISSN: 1432-198X [Electronic] Germany
• PMID: 25822460 (Publication Type: Case Reports, Journal Article)

Chemical References

• LRP2 protein, human
• Low Density Lipoprotein Receptor-Related Protein-2
• Receptors, Cell Surface
• intrinsic factor-cobalamin receptor
• Carbonic Anhydrase III

Topics

• Agenesis of Corpus Callosum (diagnosis, genetics, physiopathology, urine)
• Biopsy
• Carbonic Anhydrase III (urine)
• Child, Preschool
• DNA Mutational Analysis
• Endocytosis
• Female
• Genetic Predisposition to Disease
• Hearing Loss, Sensorineural (diagnosis, genetics, physiopathology, urine)
• Hernias, Diaphragmatic, Congenital (diagnosis, genetics, physiopathology, urine)
• Humans
• Immunohistochemistry
• Kidney Tubules, Proximal (metabolism, physiopathology, ultrastructure)
• Low Density Lipoprotein Receptor-Related Protein-2 (genetics)
• Microscopy, Electron
• Mutation
• Myopia (diagnosis, genetics, physiopathology, urine)
• Phenotype
• Predictive Value of Tests
• Prognosis
• Proteinuria (diagnosis, genetics, physiopathology, urine)
• Receptors, Cell Surface (metabolism)
• Renal Tubular Transport, Inborn Errors (diagnosis, genetics, physiopathology, urine)