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Implication de la cubiline et du récepteur du facteur intrinsèque dans la physiopathologie moléculaire de la malabsorption sélective congénitale de la vitamine B12 (syndrome de Gräsbeck-Imerslund)

Abstract : Vitamin B12 (cobalamin, Cbl) deficiencies have multiple origins. In the present study, we have focused on selective congenital mal absorptions only affecting the ileal uptake of Cbl and generally described as the Gräsbeck-Imerslund syndrome. The receptor for intrinsic factor-vitamin B12 (IFCR) is located in the ileum but also in the renal proximal tubules and plays a role in the physiopathology of this syndrome. Binding activity and affinity of the receptor for IF-Cbl complex can be both assessed from homogenates of ileal biopsies and samples of concentrated urine. A decreased binding activity of the urinary IFCR has been correlated to the syndrome in most of the cases reported in Europe. Recently, Cubilin, a multiligand receptor expressed in the ileum and the kidney was identified and assumed to be IFCR. Two mutations affecting the cubilin gene have been discovered in a Finnish population. We have investigated IFCR in five patients from diverse geographie areas, all suffering from the Grasbeck syndrome. We have systematically compared both the binding activity of urinary IFCR and the potential occurrence of mutations in some functional domains of cubilin such as IF-Cbl binding site and the putative membrane-anchoring domain. No mutation was found among the 5 patients. However, there is a discrepancy between the receptor excretion level measured by Western blot and its binding activity evaluated using the Scatchard method. Furthermore, other proteins that might be implicated in the receptor-mediated endocytosis of the receptor have been purified using affinity chromatography. In conclusion, our results suggest that cubilin is not the only protein involved in the physiopathology of this syndrome.
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Theses
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http://docnum.univ-lorraine.fr/prive/SCD_T_2001_0305_CHERY.pdf
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https://hal.univ-lorraine.fr/tel-01747041
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Submitted on : Thursday, March 29, 2018 - 10:49:57 AM
Last modification on : Monday, December 14, 2020 - 2:15:06 PM

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  • HAL Id : tel-01747041, version 1

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Céline Chery. Implication de la cubiline et du récepteur du facteur intrinsèque dans la physiopathologie moléculaire de la malabsorption sélective congénitale de la vitamine B12 (syndrome de Gräsbeck-Imerslund). Autre. Université Henri Poincaré - Nancy 1, 2001. Français. ⟨NNT : 2001NAN10305⟩. ⟨tel-01747041⟩

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