Gastroenterology

Gastroenterology

Volume 116, Issue 6, June 1999, Pages 1409-1412
Gastroenterology

Liver, Pancreas, and Biliary Tract
A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote

https://doi.org/10.1016/S0016-5085(99)70505-6Get rights and content

Abstract

Background & Aims: Most patients with genetic hemochromatosis are homozygous for a single mutation of the HFE gene (C282Y). There is a second mutation, H63D, but its role in iron overload is less conclusive. The aim of this study was to investigate the basis of iron overload in a patient with classical hemochromatosis who was only heterozygous for C282Y and negative for H63D. Methods: Genotype for the C282Y, H63D, and S65C mutations of HFE was determined in patient RFH, his family members, and 365 controls. The HFE gene was sequenced in patient RFH. Allele-specific reverse-transcription polymerase chain reaction was performed to investigate RNA splicing. Allele frequency was determined by allele-specific oligonucleotide hybridization. Results: The patient is compound heterozygous for C282Y and a novel splice site mutation (IVS3 + 1G → T). His sister has an identical genotype and elevated serum ferritin and transferrin saturation. The novel mutation functionally alters messenger RNA splicing, causing obligate skipping of exon 3. However, the IVS3 + 1G → T mutation was found to be rare and was not detected in 630 control European chromosomes. Conclusions: IVS3 + 1G → T in the compound heterozygous state with C282Y results in iron overload that can progress to a severe phenotype of classical hemochromatosis. The demonstration of IVS3 +1G → T highlights the possibility of other rare HFE mutations, particularly in C282Y heterozygotes with iron overload.

GASTROENTEROLOGY 1999;116:1409-1412

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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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.

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