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Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients

Abstract : Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type4Aversus type 4B). However, the vast majority ofSLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance ofcombining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.
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https://hal.archives-ouvertes.fr/hal-01057059
Contributor : Danielle Thomas <>
Submitted on : Thursday, August 21, 2014 - 12:01:51 PM
Last modification on : Tuesday, December 8, 2020 - 3:34:34 AM

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Isabelle Callebaut, Rozenn Joubrel, Serge Pissard, Caroline Kannengiesser, Victoria Gerolami, et al.. Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients. Human Molecular Genetics, Oxford University Press (OUP), 2014, 23 (17), pp.4479-4490. ⟨10.1093/hmg/ddu160⟩. ⟨hal-01057059⟩

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