Phenotypic and functional data confirm causality of the recently identified hemojuvelin p.r176c missense mutation

Abstract

Phenotypic and functional data confirm causality of the recently identified hemojuvelin p.r176c missense mutationIn the present study, we correlate homozygosity for the very recently identified HJV p.R176C substitution with a juvenile hemochromatosis phenotype. We also show that the p.R176C variant fails to up-regulate the hepcidin promoter activity. Altogether, our results definitively show the R176C amino-acid change to be a novel hemojuvelin loss-of-function mutation. Haematologica 2007; 92:1262 92: -1263 Juvenile hemochromatosis (JH) differs from typical HFErelated hemochromatosis in that it affects both sexes equally, is linked to a faster iron deposition in parenchymal cells, causes clinical symptoms in the second and third decades of life, and, although liver dysfunction is also part of the syndrome, is associated with a more frequent presentation of hypogonadism and cardiomyopathy. In the absence of treatment, JH patients may succumb to heart failure before the age of 30.1 JH is genetically heterogeneous since it can be associated with mutations in the HJV gene, which encodes hemojuvelin (OMIM 608374), and in the HAMP gene, which encodes hepcidin (OMIM 606464).2 Very recently, Aguilar-Martinez and co-workers have reported the combination of the known p.G320V pathogenic mutation together with a newly identified p.R176C substitution in the HJV gene of a 5-year-old girl of European descent. The girl displayed elevated iron indices without presenting clinical manifestations of juvenile hemochromatosis. 3 We simultaneously detected the p.R176C substitution at the homozygous state in a 17-year-old female of French Caucasian ancestry. At diagnosis, the teenager presented with a transferrin saturation of 97% and a serum ferritin concentration above 2,000 µg/L. Clinical manifestations included astheny, arthralgy, hypogonadotrophic hypogonadism and hepatomegaly. A liver biopsy specimen confirmed diagnosis of hemochromatosis and showed micronoduleous cirrhosis. It should be stressed that, consistent with their respective genetic states (i.e. heterozygous or negative for the p.R176C substitution), relatives had normal iron indices (Figure 1). On the other hand, the p.R176C amino-acid change was not detected in 256 healthy blood donors from the same geographical area. Written informed consent was obtained from patients and controls before blood samples were taken.Hepcidin is a 25 amino-acid peptide that is mainly synthesized by hepatocytes and plays a central role in iron homeostasis. Through its ability to bind the ferroportin iron exporter and cause its degradation, hepcidin determines the amount of iron that must be mobilized from macrophages, enterocytes and hepatocytes to meet the body's needs. 4 As expected from the initial observation of reduced hepcidin levels in patients with HJV mutations, 2 and subsequently in HJV knock-out mice, 5 there is a strong functional relationship between the two gene products involved in JH. While some important aspects still need to be clarified, a major advance towards a better...

Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review

“…G320V [5, 12, 16, 18–20, 22, 26–28, 34, 36, 37, 39, 40, 46, 54–65] and L101P [18, 26, 27, 36], the most commonly reported substitutions, were restricted to Caucasian ancestry. Among those reported in Caucasians more than three times, D149fs, R176C, and G336* were observed in Italian, French, or Indian cases only [8, 18, 19, 22, 26, 45, 66], suggesting that cases originating from different nations had their own recurrent mutations. [Q6H; C321*] in cis was the predominant genotype in Chinese HJV -HH [9–11, 29].…”

Variable expressivity of HJV related hemochromatosis: “Juvenile” hemochromatosis?

“…patients 2 and 7 were compound heterozygous, respectively p.Arg41Pro/p.Arg176Cys and p.Leu101Pro/p.Ala384Val. The p.Arg176Cys variant had previously been described at a homozygous state in a 17-years old patient (28) and at a heterozygous state associated with the p.Gly320Val in a 5-years old patient (10). In the first description of the p.Leu101Pro variant, homozygous patients were aged from 8 to 23 years old (8).…”

Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes

“…Other very rare or private HFE variants have been reported in affected individuals, contributing to the HH genetic heterogeneity [3][4][5][6][7][8][9][10]. Moreover, an association of HH with other genes, such as the transferrin receptor 2 (TFR2) [11][12][13][14][15][16], the hemojuvelin (HJV) [17][18][19][20][21][22][23][24][25] and the hepcidin (HAMP) [14,[26][27][28][29][30][31] genes, has also been documented. These latter two genes are mainly associated with the juvenile form of the disease (Juvenile Hemochromatosis, JH).…”