Gastroenterology

Gastroenterology

Volume 122, Issue 5, May 2002, Pages 1295-1302
Gastroenterology

Clinical Research
Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene,☆☆

https://doi.org/10.1053/gast.2002.32984Get rights and content

Abstract

Background & Aims: Although most patients with hereditary hemochromatosis are homozygous for a single mutation of the HFE gene on chromosome 6p, accumulating evidence indicates that the disease is genetically heterogeneous. Type 3 hemochromatosis, recently described in 4 families, is linked to mutations of the gene encoding transferrin receptor 2 on chromosome 7q22. Here we report data from a family carrying a new mutation of the transferrin receptor 2 gene. Methods: Detailed clinical and histopathologic documentation was available for most family members. The entire coding sequence and exon/intron boundaries of the transferrin receptor 2 gene were analyzed by direct sequencing. Results: A 12-nucleotide deletion in exon 16, causing the loss of 4 amino acids (AVAQ 594–597 del), was detected at the homozygous state in the 3 patients with histologically proven iron overload. The deletion segregated with the disease within the family and was not found in 100 healthy controls. Some clinical and pathologic characteristics, such as low penetrance in the premenopausal woman, and early iron deposition in periportal hepatocytes resembled those of classic, HFE-related hemochromatosis. Conclusions: Our data support the role of the transferrin receptor 2 gene in hemochromatosis type 3 as well as its critical involvement in the maintenance of iron homeostasis in humans.

GASTROENTEROLOGY 2002;122:1295-1302

Section snippets

The family

The proband, a 32-year-old man, was referred to the Department of Clinical and Experimental Medicine at the University of Verona for reevaluation of an iron overload disease previously detected elsewhere. Clinical history showed no alcohol intake, blood transfusions, or excess oral iron intake. At the age of 16 years, the patient underwent biochemical tests for scleral jaundice. Increased serum levels of bilirubin (2.8 mg/dL, predominantly unconjugated) and iron (230 μg/dL) were detected.

Clinical findings

The first liver biopsy specimen of the proband was recovered and reviewed. Histopathologic evaluation showed normal lobular architecture, no significant fibrosis, and hepatocellular hemosiderin deposits of grade III according to Scheuer et al.28 (Figure 2A and B).

. The first liver biopsy specimen of the proband (II:1) performed in 1988 at another hospital. (A) A well-preserved portal tract; the cytoplasm of periportal hepatocytes is engulfed by brown pigment (H&E; original magnification 250×). (B

Discussion

The present description of a family carrying a new mutation of the TFR2 gene further supports the role of this gene as causative for HH type 3. Affected members from this family showed an early-onset disease because iron overload was detected before the age of 30 years in all of them, including the woman (II:4). This feature and the clinical findings of patient II:2 were apparently consistent with the diagnosis of juvenile hemochromatosis, the most severe form of HH, characterized by rapidly

Acknowledgements

The authors thank the members of the family (especially the proband), Dr. Alberto Piperno from the University of Milano-Bicocca for measuring hepatic iron concentration, and Dr. Daniela Bertuzzi, on behalf of the blood banks of San Bonifacio and Verona, for their cooperation.

References (39)

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Address requests for reprints to: Domenico Girelli, M.D., Ph.D., Department of Clinical and Experimental Medicine, University of Verona, Policlinico G.B. Rossi, 37134 Verona, Italy. e-mail: [email protected]; fax: (39) 45-580111.

☆☆

Supported by Telethon grants E.749 (to D.G.) and GP 0255Y01 (to C.C.) and by the European Community (contract QLRT-1999-02237).

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