Analysis of Genes Implicated in Iron Regulation in Individuals Presenting with Primary Iron Overload

Overview

Journal Hum Genet

Specialty Genetics

Date 2004 Sep 1

PMID 15338274

Citations 11

Authors

Monique G Zaahl

Alison T Merryweather-Clarke

Maritha J Kotze

Schalk van der Merwe

Louise Warnich

Kathryn J H Robson

Affiliations

Soon will be listed here.

Abstract

Extensive investigation into the molecular basis of iron overload disorders has provided new insights into the complexity of iron metabolism and related cellular pathways. The possible involvement of genes affecting iron homeostasis, including HFE, SLC40A1, HAMP and CYBRD1, was investigated in individuals who were referred for confirmation or exclusion of a diagnosis of haemochromatosis, but who tested negative or were heterozygous for the causative HFE mutation, C282Y. Denaturing high performance liquid chromatography analysis of these genes revealed a unique spectrum of mutations in the South African study population, including 67 unrelated patients and 70 population-matched controls. Two novel CYBRD1 gene mutations, R226H and IVS1-4C-->G, were identified in 11% of South African Caucasian patient referrals. We identified a novel D270V mutation in the SLC40A1 gene in a Black South African female with iron overload. These mutations were absent in the control population. In Africans with iron overload not related to the HFE gene, the possible involvement of the SLC40A1 and CYBRD1 genes was demonstrated for the first time. This study confirms the genetic heterogeneity of haemochromatosis and highlights the significance of CYBRD1 mutations in relation to iron overload.

Citing Articles

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References

Caceres J, Stamm S, Helfman D, Krainer A . Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors. Science. 1994; 265(5179):1706-9. DOI: 10.1126/science.8085156. View

Pointon J, Wallace D, Merryweather-Clarke A, Robson K . Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test. 2000; 4(2):151-61. DOI: 10.1089/10906570050114867. View

Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J . Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2002; 33(1):21-2. DOI: 10.1038/ng1053. View

Njajou O, Vaessen N, Joosse M, Berghuis B, van Dongen J, Breuning M . A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001; 28(3):213-4. DOI: 10.1038/90038. View

Padgett R, Grabowski P, Konarska M, Seiler S, Sharp P . Splicing of messenger RNA precursors. Annu Rev Biochem. 1986; 55:1119-50. DOI: 10.1146/annurev.bi.55.070186.005351. View

Beutler E, West C . New diallelic markers in the HLA region of chromosome 6. Blood Cells Mol Dis. 1997; 23(2):219-29. DOI: 10.1006/bcmd.1997.0139. View

Hohler T, Leininger S, Schneider P . A new polymorphism in the human HFE gene. Immunogenetics. 1999; 49(9):823-4. DOI: 10.1007/s002510050559. View

Zaahl M, Robson K, Warnich L, Kotze M . Expression of the SLC11A1 (NRAMP1) 5'-(GT)n repeat: opposite effect in the presence of -237C-->T. Blood Cells Mol Dis. 2004; 33(1):45-50. DOI: 10.1016/j.bcmd.2004.04.003. View

Soriano N, Ferran H, Wojcik F, Palierne E, Tamim S, Jovelin T . Identification of 96 single nucleotide polymorphisms in eight genes involved in iron metabolism: efficiency of bioinformatic extraction compared with a systematic sequencing approach. Hum Genet. 2001; 109(4):393-401. DOI: 10.1007/s004390100599. View

10.

Borrego S, Saez M, Ruiz A, Gimm O, Lopez-Alonso M, Antinolo G . Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. J Med Genet. 1999; 36(10):771-4. PMC: 1734238. DOI: 10.1136/jmg.36.10.771. View

11.

Cambien F, Poirier O, Nicaud V, Herrmann S, Mallet C, Ricard S . Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet. 1999; 65(1):183-91. PMC: 1378089. DOI: 10.1086/302448. View

12.

Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M . The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000; 25(1):14-5. DOI: 10.1038/75534. View

13.

Roetto A, Merryweather-Clarke A, Daraio F, Livesey K, Pointon J, Barbabietola G . A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. Blood. 2002; 100(2):733-4. DOI: 10.1182/blood-2002-03-0693. View

14.

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View

15.

Feder J, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy D, Basava A . A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996; 13(4):399-408. DOI: 10.1038/ng0896-399. View

16.

Jouanolle A, Douabin-Gicquel V, Halimi C, Loreal O, Fergelot P, Delacour T . Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload. J Hepatol. 2003; 39(2):286-9. DOI: 10.1016/s0168-8278(03)00148-x. View

17.

McKie A, Latunde-Dada G, Miret S, McGregor J, Anderson G, Vulpe C . Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans. 2002; 30(4):722-4. DOI: 10.1042/bst0300722. View

18.

Yang Z, Zhu T, Ma G, Yin H, Qian W, Zhang F . Apolipoprotein E polymorphism in the early onset of coronary heart disease. Chin Med J (Engl). 2002; 114(9):983-5. View

19.

Rhodes D, Raha-Chowdhury R, Cox T, Trowsdale J . Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J Med Genet. 1997; 34(9):761-4. PMC: 1051063. DOI: 10.1136/jmg.34.9.761. View

20.

Bacon B, Sadiq S . Hereditary hemochromatosis: presentation and diagnosis in the 1990s. Am J Gastroenterol. 1997; 92(5):784-9. View