Liver, Pancreas, and Biliary TractA novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote☆
Section snippets
Patients
Patient RFH presented in 1983 at the age of 37 years with malaise, polydipsia, and polyuria, and insulin-dependent diabetes mellitus was diagnosed. He also had loss of libido. Examination showed bilateral gynecomastia, hepatosplenomegaly, and testicular atrophy. There was no history of excess alcohol intake, hematologic disease, blood transfusions, or excess oral iron intake. Investigations showed a low white cell and platelet count consistent with hypersplenism and normal bilirubin,
Identification of a splice site mutation in the HFE gene
When mutation analysis became available in 1996, patient RFH was found to be heterozygous only for C282Y. Previous studies had ruled out major chromosomal rearrangement around the HFE gene.12 Sequence analysis identified a heterozygous G-to-T change at position +1 of intron 3 (IVS3 + 1G → T). This novel mutation alters the invariant G at position +1 of the 5' splice site. This nucleotide is highly conserved in functional splice sites, and mutations at this position cause many human genetic
Discussion
We describe a unique case of classical GH in a patient compound heterozygous for C282Y and a novel splice site mutation of HFE. His sister is also a compound heterozygote for C282Y and IVS3 + 1G → T. She has elevated serum ferritin and transferrin saturation and has been advised to undergo therapeutic venesection. There has been considerable debate as to whether GH is defined by phenotypic or genotypic criteria. As illustrated by this case, when other causes of iron overload have been excluded,
Acknowledgements
The authors thank Jason Partridge, Darek Górecki, J. Paul Simons, and Marita Pohlschmidt for helpful discussion and support; Saleem Mohammed for expert advice on RNA preparations; Harriet Gordon, Marsha Morgan, George Webster, Kasra Saeb-Parsy, Geoff Dusheiko, Alain Hovnanian, Adrian Bomford, Michael Clare, Antonello Pietrangelo, Pram Mistry, Andrew Burroughs, Victor Hoffbrand, and Gerald Smith for patient and control samples; Hugh Taylor for patient referral; and Susan Davies for the
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Haemochromatosis
2016, The LancetCitation Excerpt :On the basis of a large study of 41 038 individuals attending a health appraisal clinic in the USA by Beutler and colleagues,8 it can be assumed that other genotypes (p.Cys282Tyr heterozygosity, His63Asp heterozygosity, and His63Asp homozygosity) do not result in clinically relevant modifications of iron metabolism even if they are associated with a slight increase in serum ferritin concentrations or transferrin saturation when considering large populations. Some exceptional private mutations (rare genetic mutations that are usually found only in a single family or a small population) have been reported, which, when associated with p.Cys282Tyr heterozygosity, might be responsible for severe iron overload.47,48 The classic well known clinical manifestations of haemochromatosis are hepatic cirrhosis, diabetes, and skin pigmentation (figure 3).49
Iron Metabolism and Related Disorders
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsEASL clinical practice guidelines for HFE hemochromatosis
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Address requests for reprints to: Ann Walker, Ph.D., Department of Medicine, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, England. e-mail: [email protected]; fax: (44) 171-830-2631.