Hemochromatosis mutations C282Y and H63D in ‘cis’ phase

Best, LG; Harris, PE; Spriggs, EL

doi:10.1034/j.1399-0004.2001.600111.x

Cited by 28 publications

(12 citation statements)

References 25 publications

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“…The association of both the H63D and E168Q mutations on the same chromosome as shown in this family, confirms that multiple mutations can occur in the same HFE allele, as previously reported by Thorstensen et al (2000), Best et al (2001), andLucotte et al (2001).…”

Section: Discussionsupporting

confidence: 89%

“…This mutation is located in the a1-domain of the HFE protein, which corresponds to the antigen-binding groove of the MHC class I molecule and does not have any effect on the bond with b 2 -microglobulin: rather it results in a decreased affinity for transferrin by the Tfr Rosmorduc et al, 2000) but to a less marked degree than for the C282Y mutation. These two mutations have rarely been reported to occur within the same DNA strand (Thorstensen et al, 2000;Best et al, 2001;Lucotte et al, 2001).…”

Section: Introductionmentioning

confidence: 94%

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A Very Rare Association of Three Mutations of theHFEGene for Hemochromatosis

et al. 2002

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In the present paper, we describe a patient who is a compound heterozygote for three mutations in the HFE gene: C282Y, H63D, and E168Q. The patient's mother carries two copies of H63D and one copy of E168Q; the patient's father is heterozygous for C282Y. The family study indicates that the patient, as well as his sister, a maternal uncle, and a first cousin, all have inherited a single HFE allele that contains two mutations H63D and E168Q. The clinical symptoms and laboratory findings of the patient and his relatives are consistent with the conclusion that the E168Q mutation by itself is unlikely to result in hemochromatosis.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 94%

A Very Rare Association of Three Mutations of theHFEGene for Hemochromatosis

et al. 2002

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“…This is because C282Y and H63D are very rarely found in the same HFE gene25 26 and the high frequency of C282Y in the families with haemochromatosis is associated with a reduced frequency of H63D. In the group with ?HH the frequency of homozygosity for H63D was significantly higher than in the control group (3.9 and 2.5%, p = 0.036) but this frequency did not increase with additional evidence of iron overload.…”

Section: Resultsmentioning

confidence: 99%

Heteroduplex analysis for the three common HFE variants: methodology, reliablity and analysis of over 5000 requests for testing

Kingston

Bowen²,

Sweeney³

et al. 2006

J Clin Pathol

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Objective: To describe the analysis of over 5300 patient samples for the HFE genotype. Methods: Blood samples received from hospitals in England, Wales and Ireland were analysed with a single, multiplex PCR using heteroduplex generators for the C282Y, H63D and S65C variants of the HFE gene. PCR products labelled with fluorescent dyes were analysed by capillary electrophoresis. Genotype frequencies were analysed according to the reasons given for testing. Results: Analysis of 400 samples sent in duplicate revealed one error that was associated with reporting rather than the methodology. Of 5327 samples received, 1122 were for family testing, 2470 for diagnostic testing and in 1735 cases no reason was given. Overall, homozygosity for C282Y was found in 14% of samples received for family testing and in 16% of the remaining samples. Clinical indications such as ''liver disease'' were of little predictive value for homozygosity for C282Y, but this increased if a raised serum ferritin concentration or transferrin saturation was indicated. When the diagnosis was iron overload, 39% of subjects tested were homozygous for C282Y. Compound heterozygosity (C282Y/H63D) was more frequent than in the general population but the frequency was not further increased in subjects for whom there was a diagnosis of iron overload. The frequencies of heterozygosity for H63D or S65C and homozygosity for H63D were not significantly increased in any group compared with the general population frequency.Conclusion: These results demonstrate the reliability of the methodology and confirm the difficulty of identifying genetic haemochromatosis purely on the basis of clinical suspicion that haemochromatosis may be responsible for liver disease, diabetes or arthritis. 2 Once diagnosed, HH is readily treatable by the means of venesection and, provided complications have not arisen, life expectancy is not reduced.3-5 The allele frequency of HFE C282Y in people of northern European origin in the UK is about 8% with about one in seven people being heterozygous, and one in 150 being homozygous for the C282Y allele. 6 The frequency, availability of a genetic test and an effective treatment have led to pressure to implement population screening 7 although there were always concerns about the clinical penetrance of HFE mutations. 8 These concerns were justified as it is now clear that although most men, and about 50% of women, who are homozygous for C282Y will show evidence of iron accumulation (a raised transferrin saturation) the clinical penetrance of homozygosity for C282Y is low.9-11

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“…The favoured model describes the iron uptake at the basolateral membrane of duodenal crypt cells via the transferrin 1-receptor (TfR1) that needs the interaction with the wildtype HFE-molecule to guarantee the balance between absorption, storage and consumption [2,3] . Further allelic variants in the HFE gene have been described but seem to lack clinical relevance [4][5][6] . Our patient presented with an additional hereditary disease, PCT.…”

Section: Discussionmentioning

confidence: 99%

An unhappy triad: Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-A case report

Mogl

Pascher²,

Presser³

et al. 2007

WJG

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Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma (HCC). Hemosiderosis has also been described to trigger carcinogenesis. A significant iron overload, as found in hereditary hemochromatosis (HHC), is a risk factor for HCC and may also promote the symptoms of porphyria cutanea tarda (PCT). A 68-year old male patient presented to our clinic with a suspected HCC, elevated alpha-fetoprotein but normal liver function tests. He reported a 25 year-old history of vitiligo upon exposure to sunlight. The patient underwent an extended left hemihepatectomy, and the recovery was uneventful, with the exception of a persistent hyperbilirubinemia. Perfusion problems and extrahepatic cholestasis were ruled out by CT-scan with angiography and MR-cholangiopancreatography. However, MRI showed an iron overload. Histology confirmed the HCC (pT3, pN0, G3, R0) and revealed a portal fibrosis and hemosiderosis. Based on the skin lesions we suspected a PCT that was confirmed by laboratory tests showing elevated porphyrin, uroporphyrin, coproporphyrin and porphobilinogen. Concurrently, molecular diagnostics revealed homozygosity for the C282Y mutation within the hemochromatosis HFE gene. After phlebotomy and normalization of liver function tests the patient was discharged. This is the first case ever showing the unusual combination of HCC in a fibrotic liver with HHC and PCT. This diagnosis not only warrants oncological follow-up but also symptomatic therapy to normalize iron metabolism and thereby improve liver function and alleviate the symptoms of HHC and PCT. Thus progression of fibrosis may be prevented and liver regeneration supported.

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Hemochromatosis mutations C282Y and H63D in ‘cis’ phase

Cited by 28 publications

References 25 publications

A Very Rare Association of Three Mutations of theHFEGene for Hemochromatosis

A Very Rare Association of Three Mutations of theHFEGene for Hemochromatosis

Heteroduplex analysis for the three common HFE variants: methodology, reliablity and analysis of over 5000 requests for testing

An unhappy triad: Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-A case report

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