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• W2053185571 abstract "HFE-related haemochromatosis is an inherited iron metabolism disorder leading to progressive iron accumulation in parenchymal cells. Over time, cell iron excess may cause tissue damage and severe clinical complications, including cirrhosis, hepatocellular carcinoma and cardiomyopathy. Patients are predominantly of northern European origin and overwhelmingly homozygous for the HFE C282Y mutation (Anderson & McLaren, 2012). We previously reported a large 32·7 kb deletion, removing the entire HFE gene resulting from an Alu-mediated homologous recombination (Fig 1C) (Le Gac et al, 2008). It is noteworthy that HFE deletion is the most common cause of haemochromatosis in Sardinia, apparently due to a founder effect (Le Gac et al, 2010). To date, no other large HFE deletions have been reported. Here, we report the characterization of a new HFE deletion in a male patient with suspected haemochromatosis. Age at onset was 61 years. Clinical symptoms included fatigue, arthritis (chondrocalcinosis) and type-1 diabetes. Iron parameters were evaluated before therapeutic phlebotomy. They showed a high transferrin saturation level (85%) and a moderate increase of serum ferritin (600 μg/l). The patient reported no history of viral hepatitis, alcohol abuse, haematological disease or blood transfusion. He denied consanguinity in his parents. It should be noted, however, that the patient was born in a rural area in Corsica, which is the most mountainous island in the Mediterranean. We first screened for the commonest C282Y mutation by real-time polymerase chain reaction (PCR). Failure to amplify HFE exon 4, containing the C282Y mutation, suggested a homozygous genomic deletion. We attempted to genotype the DNA for the ‘Sardinian HFE deletion’ using a pre-established rearrangement-specific PCR (Le Gac et al, 2008); however, this yielded no products, indicating a different chromosomal rearrangement. Array comparative genomic hybridization (array-CGH) finally revealed a ~56 kb deletion involving HFE and several histone-coding genes (Fig 1A). Further analyses sought to capture the aberrant chromosomal junction and characterize the deletion at nucleotide level: it removed 56 097 nucleotides, from chr6:26 042 836 (telomeric end) to chr6:26 098 934 (centromeric end). Intriguingly, this deletion was also found to result from Alu-mediated recombination (Fig 1B). Based upon the current knowledge of mutational mechanisms (Cooper et al, 2011), we surmized that the genomic region affected by the two deletions might show unique sequence features. Transposable elements (TE), which comprise about 45% of the total human genome, are a tremendous source of chromosomal rearrangement (Batzer & Deininger, 2002). Notably, high total TE content (>40%) increases the incidence of gross deletions (Van Zelm et al, 2008). Importantly, genomic instability due to TE is not restricted to gene-poor regions: disease gene disruption is frequently caused by ectopic recombination between two transposable elements, as in several different Alu-mediated recombinations found at the VHL (Von Hippel-Lindau disease) and EPCAM-MSH2 (Lynch syndrome) loci (Franke et al, 2009; Kuiper et al, 2011). These observations prompted us to explore the TE pattern in the chromosome 6 region flanking HFE. HFE is located in the major human histone gene cluster, which covers about 2·3 Mb, with 55 histone gene copies. As illustrated in Fig 1C, HFE is embedded in a short chromosomal section (300 kb) that is very dense in histone genes. RepeatMasker (http://www.repeatmasker.org) revealed that the four TE classes (short interspersed elements (SINE), long interspersed elements (LINE), long terminal repeats (LTR) and DNA transposons) were differently distributed across the chromosomal region of interest. Most importantly, Alu sequences were the most abundant repetitive elements, 1·7-fold denser than in the human genome (17·8% vs. 10·5%; Fig 1D). Likewise, the 57 321 bp genomic DNA sequence encompassing the two HFE gross deletions showed 50·1% total TE density and 16·8% Alu density. Figure 1C shows a physical map of the DNA segment, with a total 35 Alu repeats organized in both directions and Alu elements once every 1·6 kb: i.e., 1·825-fold enrichment compared with the average for the whole human genome, where Alu elements occur once every 3 kb (Lander et al, 2001). In conclusion, we have reported two large deletions at the HFE locus and revealed a common molecular basis relying on Alu-mediated unequal crossover events. In line with previous reports studying the correlation between gross deletions at cancer genes loci and the density of transposable elements, we evidenced a high ratio of Alu repeats around HFE. It remains unclear whether or not this particular environment determines a chromosomal instability. Nevertheless, the evidence shown here suggests that HFE deletions could represent an underestimated cause of haemochromatosis. Grant support: Etablissement Français du Sang (EFS) and the Institut National de la Santé et de la Recherche Médicale (Inserm), France. Chandran Ka, Isabelle Gourlaouen and Sylvia Quemener performed the molecular analyses. Christophe Ronsin, Simone Massonnet and Jean-Paul Thérond provided clinical data. Jian-Min Chen helped in elucidating the mutational mechanism and revised the manuscript. Gérald Le Gac and Claude Férec designed the study and obtained funding. Gérald Le Gac wrote the paper. All authors approved the final manuscript. The authors declare no conflict of interest." @default.
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• W2053185571 date "2014-10-04" @default.
• W2053185571 modified "2023-10-18" @default.
• W2053185571 title "Characterization of the second HFE gross deletion highlights the potential importance of Alu-mediated recombination in haemochromatosis" @default.
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• W2053185571 doi "https://doi.org/10.1111/bjh.13145" @default.
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