Detailed investigations of proximal tubular function in Imerslund-Grasbeck syndrome.

Abstract : BACKGROUND: Imerslund-Grasbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. METHODS: Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. RESULTS: Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin d-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. CONCLUSIONS: In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.
Type de document :
Article dans une revue
BMC Medical Genetics, BioMed Central, 2013, 14 (1), pp.111. 〈10.1186/1471-2350-14-111〉
Liste complète des métadonnées

Littérature citée [52 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00904107
Contributeur : Ed. Bmc <>
Soumis le : mercredi 13 novembre 2013 - 17:08:13
Dernière modification le : mercredi 21 mars 2018 - 18:57:36
Document(s) archivé(s) le : vendredi 14 février 2014 - 15:51:25

Fichiers

Identifiants

Collections

UPMC | U968 | USPC

Citation

Tina Storm, Christina Zeitz, Olivier Cases, Sabine Amsellem, Pierre Verroust, et al.. Detailed investigations of proximal tubular function in Imerslund-Grasbeck syndrome.. BMC Medical Genetics, BioMed Central, 2013, 14 (1), pp.111. 〈10.1186/1471-2350-14-111〉. 〈inserm-00904107〉

Partager

Métriques

Consultations de la notice

547

Téléchargements de fichiers

411