Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration

Tina Storm; Lisbeth Tranebjærg; Carina Frykholm; Henrik Birn; Pierre J. Verroust; Tryggve Nevéus; Birgitta Sundelin; Jens Michael Hertz; Gerd Holmström; Katharina Ericson; Erik Ilsø Christensen; Rikke Nielsen

doi:10.1093/ndt/gfs462

Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration

Tina Storm, Lisbeth Tranebjærg, Carina Frykholm, Henrik Birn, Pierre J. Verroust, Tryggve Nevéus, Birgitta Sundelin, Jens Michael Hertz, Gerd Holmström, Katharina Ericson, Erik Ilsø Christensen, Rikke Nielsen

Medical Genetics Program

51 Citationer (Scopus)

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. Conclusion. sThis 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.

Originalsprog	Engelsk
Tidsskrift	Nephrology, Dialysis, Transplantation
Vol/bind	28
Udgave nummer	3
Sider (fra-til)	585-91
Antal sider	7
ISSN	0931-0509
DOI	https://doi.org/10.1093/ndt/gfs462
Status	Udgivet - mar. 2013

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10.1093/ndt/gfs462

https://academic.oup.com/ndt/article-pdf/28/3/585/17171493/gfs462.pdf

Citationsformater

Storm, T., Tranebjærg, L., Frykholm, C., Birn, H., Verroust, P. J., Nevéus, T., Sundelin, B., Hertz, J. M., Holmström, G., Ericson, K., Christensen, E. I., & Nielsen, R. (2013). Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration. Nephrology, Dialysis, Transplantation, 28(3), 585-91. https://doi.org/10.1093/ndt/gfs462

Storm, T, Tranebjærg, L, Frykholm, C, Birn, H, Verroust, PJ, Nevéus, T, Sundelin, B, Hertz, JM, Holmström, G, Ericson, K, Christensen, EI & Nielsen, R 2013, 'Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration', Nephrology, Dialysis, Transplantation, bind 28, nr. 3, s. 585-91. https://doi.org/10.1093/ndt/gfs462

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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. Conclusion. sThis 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.",

author = "Tina Storm and Lisbeth Tranebj{\ae}rg and Carina Frykholm and Henrik Birn and Verroust, {Pierre J.} and Tryggve Nev{\'e}us and Birgitta Sundelin and Hertz, {Jens Michael} and Gerd Holmstr{\"o}m and Katharina Ericson and Christensen, {Erik Ils{\o}} and Rikke Nielsen",

year = "2013",

month = mar,

doi = "10.1093/ndt/gfs462",

language = "English",

volume = "28",

pages = "585--91",

journal = "Nephrology, Dialysis, Transplantation",

issn = "0931-0509",

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TY - JOUR

T1 - Renal phenotypic investigations of megalin-deficient patients

T2 - novel insights into tubular proteinuria and albumin filtration

AU - Storm, Tina

AU - Tranebjærg, Lisbeth

AU - Frykholm, Carina

AU - Birn, Henrik

AU - Verroust, Pierre J.

AU - Nevéus, Tryggve

AU - Sundelin, Birgitta

AU - Hertz, Jens Michael

AU - Holmström, Gerd

AU - Ericson, Katharina

AU - Christensen, Erik Ilsø

AU - Nielsen, Rikke

PY - 2013/3

Y1 - 2013/3

N2 - 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. Conclusion. sThis 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.

AB - 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. Conclusion. sThis 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.

U2 - 10.1093/ndt/gfs462

DO - 10.1093/ndt/gfs462

M3 - Journal article

C2 - 23048173

SN - 0931-0509

VL - 28

SP - 585

EP - 591

JO - Nephrology, Dialysis, Transplantation

JF - Nephrology, Dialysis, Transplantation

IS - 3

ER -

Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration

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