Reply to: SLC40A1 -R178G mutation and ferroportin disease
Authors: Roman Mayr, Heinz Zoller
Journal: Journal of Hepatology (2011)

SLC40A1-R178G mutation and ferroportin diseaseJournal of HepatologyVol. 55Issue 3PreviewIn their excellent systematic meta-analysis on the ferroportin disease, recently published in the Journal of Hepatology, Mayr et al. present in detail all the described SLC40A1 gene alterations and their relationship with disease phenotype [1]. The prevalence of these alterations in the general population is also presented, indicating that a few of them are polymorphisms with an unknown, as yet, biological significance. Full-Text PDF Open AccessSLC40A1-R178G or R178Q and ferroportin disease? A call for vigilance in mutation reportingJournal of HepatologyVol. 59Issue 2PreviewI refer to a previous Letter to the Editor and its reply [1] regarding the excellent meta-analysis on ferroportin disease performed by Mayr et al. in the Journal of Hepatology in November 2010 [2]. The SLC40A1-R178G mutation is discussed and whether it is a disease-causing mutation with incomplete penetrance or a polymorphism. Upon further inspection of the original report by Speletas et al., describing the R178G mutation in a Greek family, published in the journal Blood Cell Molecules and Diseases in 2008 [3], I have come to the conclusion that an error was made in the designation of this mutation. Full-Text PDF Open AccessReply to: “SLC40A1-R178G or R178Q and ferroportin disease? A call for vigilance in mutation reporting”Journal of HepatologyVol. 59Issue 2PreviewWe appreciate the observation by Dr. Wallace uncovering our error in citing unwittingly the nomenclature of amino acid alteration of the mutation g.963G>A (according to the NCBI reference sequence NM_014585 ) of SLC40A1 gene, as R178G (Arg178Gly) instead of R178Q (Arg178Gln). An Erratum has already been submitted in concern to our initial publication [1]. We have to emphasize that all the data presented in both our initial publication describing this alteration and in the Letter to the Editor [2] are absolutely correct. Full-Text PDF Open Access Clearly, the observation that R178G was not found in 253 ethnically matched bone marrow donors, supports Dr. Speletas’ and his colleagues’ notion that R178G is a rare sequence variant. The concept that R178G is a disease causing mutation is challenged by the apparently incomplete penetrance of this mutation in the family reported. Additional clinical information provided in the letter above further supports the notion that the index case and her mother are affected by an iron storage disease that can be regarded as a genuine ferroportin disease. However, absence of hyperferritinemia in the oldest individual identified with the R178G mutation can either be interpreted as incomplete penetrance or as evidence against R178G being a disease causing mutation. This raises an important question: When do we consider a genetic variant disease causing? In the age of genome wide association studies and whole genome sequencing, this question becomes increasingly important. The frequency of a sequence variant does not necessarily reflect the functional importance because even in ferroportin related iron overload, common polymorphisms in SLC40A1, such as Q248H, have been reported as a strong risk factor for hyperferritinemia [[1]Beutler E. Barton J.C. Felitti V.J. Gelbart T. West C. Lee P.L. et al.Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.Blood Cells Mol Dis. 2003; 31: 305-309Crossref PubMed Scopus (119) Google Scholar]. On the other hand, V72F represents a rare sequence variant that may still be of little functional consequence [[2]Pelucchi S. Mariani R. Salvioni A. Bonfadini S. Riva A. Bertola F. et al.Novel mutations of the ferroportin gene (SLC40A1): analysis of 56 consecutive patients with unexplained iron overload.Clin Genet. 2008; 73: 171-178Crossref PubMed Scopus (28) Google Scholar]. Taken together, a genetic variant is likely to be disease causing if the mutation segregates with the disease within a family and is not present in an ethnically matched population. In silico studies can provide further evidence for the functional consequence of genetic variations, which – for R178G – supports the notion that this mutation is disease causing [[3]Mayr R. Janecke A.R. Schranz M. Griffiths W.J. Vogel W. Pietrangelo A. et al.Ferroportin disease: a systematic meta-analysis of clinical and molecular findings.J Hepatol. 2010; 53: 941-949Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar]. Finally, functional and structural studies of the mutant protein in cells or knock-in animals have not been reported for R178G. Hence, the question remains whether R178G is disease causing or not. This uncertainty is paradigmatic for ferroportin disease and is expected to increase, because it remains to be resolved how to analyze millions of sequence variants detected by next generation sequencing technology [[4]Lupski J.R. Reid J.G. Gonzaga-Jauregui C. Rio Deiros D. Chen D.C. Nazareth L. et al.Whole-genome sequencing in a patient with Charcot–Marie–Tooth neuropathy.N Engl J Med. 2010; 362: 1181-1191Crossref PubMed Scopus (626) Google Scholar] that, at the threshold of entering clinical practice, can be interpreted and functionally analyzed. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.