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In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

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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.

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Acknowledgments

The authors are thankful to all members of the Department of Pediatrics at CHC Hospital for their help and helpful suggestions about this clinical case, as well as to L. Poma for skillful technical assistance. Comments and suggestions of E. Castermans (Division of Genetics, Ulg CHU, Liège, Belgium) and O. Hougrand (Department of Pathology, Ulg CHU, Liège, Belgium) were greatly appreciated. FJ is an MD Postdoctoral Fellow of the Fonds National de la Recherche Scientifique (FNRS) in the unit GIGA Cardiovascular Sciences (Prof. J-M Krzesinski and J-O Defraigne) of the University of Liège, and receives support from the FNRS (Research Credit 3309), the University of Liège (Fonds Spéciaux à la Recherche) and from the Fonds Léon Fredericq. The present study was performed after approval by the Ethics Committee of the University of Liège Hospital.

Conflict of interest

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Authors and Affiliations

  1. Division of Pediatrics, CHC Liège, Liège, Belgium

    Angélique Dachy & Laure Collard

  2. Division of Nephrology, University of Liège Hospital (Ulg CHU), Liège, Belgium

    François Paquot, Christophe Bovy & François Jouret

  3. Division of Genetics, University of Liège Hospital (Ulg CHU), Liège, Belgium

    Guillaume Debray

  4. Department of Biomedicine, University of Aarhus, Aarhus, Denmark

    Erik I. Christensen

  5. CHC Clinique de l’Espérance, Rue Saint Nicolas 447, B-4420, Montegnée, Belgium

    Laure Collard

Authors
  1. Angélique Dachy
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  2. François Paquot
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  3. Guillaume Debray
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  4. Christophe Bovy
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  5. Erik I. Christensen
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  6. Laure Collard
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  7. François Jouret
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Correspondence to Laure Collard.

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Dachy, A., Paquot, F., Debray, G. et al. In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction. Pediatr Nephrol 30, 1027–1031 (2015). https://doi.org/10.1007/s00467-014-3037-7

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  • DOI: https://doi.org/10.1007/s00467-014-3037-7

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