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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5525-5526.
CORRESPONDENCE Effect of the new HJV-L165X mutation on penetrance of HFETo the editor:We present a new homozygous truncating mutation, L165X, of the hemojuvelin gene (HJV), observed in one male patient with severe juvenile hemochromatosis (JH). Because the C282Y-variant in the hemochromatosis gene (HFE) was also common in this family, we investigated whether the inactivating mutation HJV-L165X influenced penetrance of HFE-C282Y homozygosity.
The proband, born in 1956 and diagnosed in 1972 by family screening (B III-54),1 presented with increased serum iron values and heavy iron accumulation in the hepatocytes.1,2 There was no consanguinity between his parents or grandparents,1 and linkage to HLA was excluded in his familybranch, providing the first clue of genetic heterogeneity in hemochromatosis.3 In late 2005, he provided contact information on relatives. The institutional review board approved this study and informed consent was obtained from all participants (n = 20). Non-fasting blood and urine samples from the proband and his relatives were collected between 7 and 9PMon the same day. Information on the number of phlebotomies and the time between the last phlebotomy and sample collection was provided. Urinary hepcidin was measured by mass spectometry.4 For the proband, we sequenced the hepcidin (HAMP) and HJV genes. Mutations in the HAMP gene were absent. The HJV gene was sequenced using previously reported primers.5 For exon 3 we designed new primers: Ex3a1935F 5'-GCAAACTACACTCCGATAGAG-3' and Ex3a2253R 5'-GCTGGATCATCAGGTCTTCG-3', resulting in a 319 bp product, and Ex3b2202F 5'-GACCTCGCCTTCCATTCG-3' and Ex3b2603R 5'-GAATCTCATGAGGTGGATCGG-3', leading to a 402 bp product (GenBank NT_004 434/gi:88 943 080). We observed a novel homozygous mutation in exon 3 of the HJV gene. The 494T Relatives of the proband were investigated for the HFE-C282Y and the HJV-L165X mutation by a restriction fragment length polymorphism analysis using the Ex3b2202F and Ex3b2603R primers and the restriction enzyme HpyCH4V (New England Biolabs, Ipswich, MA). HJV-L165X homozygosity was only present in the proband, while heterozygosity was common among relatives (allele frequency: 14/40 = 35.0%). Furthermore, the HFE-C282Y mutation was observed frequently (allele frequency: 27/40 = 67.5%) (Table 1). Phlebotomies were only reported in individuals later found to be homozygous for either HJV-L165X (n = 1; proband) or HFE-C282Y (n = 8). Iron indices (current and from the early seventies1,2; J. P. G., unpublished data, early 1970s) are copied into Table 1.
Current serum iron parameters are not appropriate as a measure of iron burden, as most relatives have been adequately phlebotomized. We found an alternative in the following parameters: quantity of iron removed by phlebotomies (iron removed/age),8 a rough estimate hampered by the probability that intestinal iron uptake may increase upon phlebotomy; transferrin saturation (TS) values and desferrioxamine (DFO) test results from the early seventies, before treatment; and urinary hepcidin levels, measured with our improved MS assay.4 The iron removed/age, urinary hepcidin levels, and iron indices from the early seventies were similar for HJV-heterozygotes (L165X) and the HJV-wildtypes, also when stratified by HFE genotype, indicating the absence of a clinically relevant modifying effect. Others reported HJV a modifier,9,10 although not consistently.11 Furthermore, our data agree with recent findings that HFE and HJV participate, at least partially, in distinct regulatory pathways.12 Finally, against a background of multiple small variations, we cannot exclude a minor effect of the heterozygous HJV-L165X mutation on iron homeostasis. Authorship Correspondence: B.A.C. van Dijk, Radboud University Nijmegen Medical Centre, Clinical Chemistry 441, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; e-mail: b.vandijk{at}akc.umcn.nl. Conflict-of-interest disclosure: The authors declare no competing financial interests.
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
A transversion leads to a premature stop codon at position 165 of the HJV protein: L165X. This probably leads to nonsense-mediated decay of the corresponding messenger RNA. If the aberrant message is translated, however, it would code for a protein that lacks the GPI anchor signal, such that it remains in the endoplasmic reticulum.
