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European Journal of Heart Failure 2008 10(10):1001-1006; doi:10.1016/j.ejheart.2008.07.012
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© 2008 European Society of Cardiology

A Q312X mutation in the hemojuvelin gene is associated with cardiomyopathy due to juvenile haemochromatosis

Yasuhiro Nagayoshi*, Masafumi Nakayama, Satoru Suzuki, Jun Hokamaki, Hideki Shimomura, Kenichi Tsujita, Masaya Fukuda, Takuro Yamashita, Yoshinori Nakamura, Seigo Sugiyama and Hisao Ogawa

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University Kumamoto City, Japan

* Corresponding author. Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan. Tel.: +81 96 373 5175; fax: +81 96 362 3256. E-mail address: ynagayos{at}kumamoto-u.ac.jp (Y. Nagayoshi).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background and aims: Juvenile haemochromatosis (JH) is an autosomal recessive iron disorder characterized by the early onset of secondary cardiomyopathy. The candidate modifier genes are hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP). In the Japanese population, the prevalence of JH is quite low. The influence of HJV mutation on the JH phenotype is still unclear.

Methods and results: We searched for possible mutations in a Japanese family with 2 members who were JH patients with severe heart failure. To search for possible variants in the HJV and HAMP genes, we performed direct sequencing in the family members. A homozygous nonsense mutation in exon 4 of HJV (Q312X) was identified in the JH patients and their mother. Three individuals in the family were heterozygous for this mutation. Subsequently, we evaluated the frequency of Q312X mutation in a large population (nw=361) without heart failure, using allele-specific real-time PCR assay. No Q312X mutation was detected in this population. In the patients with the homozygous HJV mutation, iron loading revealed high serum ferritin concentration with accompanying elevated transferrin iron saturation. In contrast, ferritin levels were within the normal range in individuals with the heterozygous mutation.

Conclusions: We found a nonsense mutation in the HJV gene. This mutation elevates ferritin levels and leads to JH associated with severe cardiomyopathy.

Key Words: Cardiomyopathy • Genetics • Haemochromatosis • Hemojuvelin • Iron homeostasis

Received December 2, 2007; Revised April 16, 2008; Accepted July 14, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Hereditary haemochromatosis (HH) is a metabolic disorder caused by high intestinal iron absorption. Excess iron accumulation in the parenchymal tissue leads to multiple organ damage, including the skin, liver, pancreas, endocrine glands and the heart.

Recently, there has been progress in understanding the complex factors that regulate iron homeostasis [1]. HH is a common inherited disorder, especially in people of northern European descent [2]. The Hemochromatosis and Iron-Overload Screening (HEIRS) study demonstrated that homozygosity for the C282Y mutation of the classic haemochromatosis (HFE) gene is a relatively common genetic mutation [3], occurring in 0.44% of Caucasians, but in only 0.00004% of Asians [4].

Juvenile haemochromatosis (JH) is a more rare autosomal recessive iron disorder. Since most of the published data on JH are based on case reports, its prevalence and distribution in different ethnic populations is difficult to estimate. The majority of cases published so far are in populations of European origin [5]. Early and massive iron overload in this disorder results in multiple organ damage [6]. Patients with JH often have severe congestive heart failure, together with other organ damage.

Candidate modifier genes for JH are hemojuvelin (HJV) [7] and hepcidin antimicrobial peptide (HAMP) [8]. Most cases of JH are linked to mutation of the HJV gene. To date, nearly 40 mutations of the HJV gene have been identified worldwide [9,10]. The majority of the mutations appear to be private. The G320V mutation has been found in different populations [7,11]. This mutation has been reported in Greece, Canada, France, Germany, Slovakia and Croatia. In Japan, two patients with haemochromatosis were previously reported to have the HJV mutation; however, these cases did not fulfil the criteria of JH [12].

In a preliminary study, we reported a novel nonsense HJV mutation in a Japanese family [13]. In this report, we describe a mutation in HJV and its association with secondary cardiomyopathy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study patients
A 4-generation family with 2 individuals displaying a pure JH phenotype was studied. The family pedigree is shown in Fig. 1. The patients with JH (III-1 and III-3) were diagnosed according to previously published criteria: (1) <30 years of age at presentation; (2) increased transferrin saturation and serum ferritin in the absence of known causes of secondly iron overload; (3) complications due to parenchymal iron overload including cardiomyopathy and hypogonadism [14]. Acquired causes of iron overload such as haemolysis, chronic inflammatory disease and malignant processes were excluded. Their parents were a second-cousin couple. The family resided in Kyushu, a south-western island of Japan. Two-dimensional echocardiography was performed by cardiologists to determine left ventricular ejection fraction (LVEF) in all family members. LVEF was calculated using a modified Simpson's rule.


Figure 01
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  		Fig. 1 Family pedigree. Bold numbers indicate pedigree number, and non-bold numbers indicate age. Slashes indicate deaths, squares indicate males, and circles indicate females. Affected individuals are represented by solid symbols. Individuals without pedigree numbers indicate unknown disease status.

 
We examined the frequency of the detected gene mutations in a larger population of subjects admitted consecutively to our institution between July 1984 and July 2000. This study population included 361 Japanese subjects who resided in Kyusyu (176 men and 185 women; mean age, 60 years; range, 25-86 years) with normal left ventricular function and with no coronary heart disease.

Written informed consent was obtained from all patients in the study. The study was also in agreement with the guidelines of and approved by the ethics committee of Kumamoto University Graduate School of Medical Sciences.

2.2. Endomyocardial biopsy
In JH patient III-3, an endomyocardial biopsy was performed in the left ventricle. Biopsy specimens were fixed in 10% neutral buffered formalin for light microscopic examination. The sections were stained with haematoxylin-eosin and Berlin blue stain for detection of iron deposition. For transmission electron microscopy (TEM), myocardial samples were fixed in 2.5% glutaraldehyde. After rinsing in sodium phosphate buffer, the specimens were fixed with 2% osmium tetroxide for 120 min. Next, they were dehydrated with graded concentrations of ethanol and propylene oxide and then embedded in Epoxy resin. Ultra-thin sections were cut with a diamond knife and double stained with uranyl acetate and lead citrate and then viewed with an electron microscope (H-7500; Hitachi, Tokyo, Japan).

2.3. Direct sequencing of the HJV, HAMP and other iron-associated genes
To search for possible variants in the iron-associated genes, we sequenced genomic DNA extracts from the JH patients. HJV, HAMP, HFE, transferrin receptor 2, ferroportin 1 and ceruloplasmin genes were sequenced in the JH patients. Genomic DNA was prepared from peripheral blood leukocytes by established methods [15]. In JH patient III-1, DNA was extracted from a liver specimen at autopsy. Genomic DNA was extracted and cleaned from the liver tissue using a genomic DNA purification kit, Puregene (Gentra Systems Corp., Minnesota, USA).

For analyses of the HJV and HAMP genes, the sequences of the primers used in the PCR and the direct sequencings are shown in Table 1. The HJV sequences were obtained from the GenBank NT_004434 [GenBank] . We amplified all 4 exons of the HJV gene. Amplification was performed in samples containing 100 ng of genomic DNA, 20 pmol of each primer, 0.2 mM dNTP mixture and 1.25 Units of blend Taq. After initial denaturation at 94 °C for 2 min, amplification was performed for 30 cycles at 94 °C for 1 min, 50 °C for 30 s, and 72 °C for 1 min.


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  		Table 1 Primers used for PCR and sequencing

 
The HAMP sequences were obtained from the GenBank AJ277280. We amplified all 3 exons of the HAMP gene. The PCR analyses were performed on samples containing 100 ng of genomic DNA as previous described [8,16]. We also amplified all exons of the transferrin receptor 2, ferroportin 1, HFE and ceruloplasmin genes. These sequences were obtained from the GenBank (GI 3135305, AF215636 [GenBank] , Z92910 [GenBank] and NM_000096 [GenBank] ). All the PCR products were sequenced with BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, USA) and ABI PRISM 310 Genetic Analyzer (Applied Biosystems, USA). All DNA sequences were confirmed by reading both DNA strands.

2.4. Allele-specific real-time PCR assay
We examined the detected mutation in the residual 4-generation family and control subjects utilizing the allele-specific real-time PCR assay method.

Primer and probe sequences were optimized by using Custom TaqMan Genomic Assays of Applied Biosystems (for details, see http://store.appliedbiosystems.com). Reactions were performed with the TaqMan Prism 7900HT 384 wells format. Using well-characterized isolates, we developed a method for detecting HJV mutations utilizing TaqMan chemistry and the ABI 7900HT Prism Sequence Detector. Fluorescence data were analyzed with the ABI 7900HT Prism Sequence Detector software (Applied Biosystems, California, USA.).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Clinical findings in patients with JH
In JH patient III-3, congestive heart failure associated with severe cardiomyopathy was observed at the age of 24. His older brother (III-1) died of advanced heart failure at the age of 22, and the pathologic anatomy showed remarkable iron deposits in his organs, including the heart. Abdominal computed tomography and magnetic resonance imaging (MRI) in patient III-3 suggested iron deposition in the liver, heart, pancreas and other organs. In the MRI, the low signal intensity of the left ventricle was obvious, especially in the subepicardial half of the myocardial wall. Serum gonadotropin levels were not detectible. The patient complained of decreased libido, decreased sperm and failure of ejaculation.

We started monthly phlebotomy with monitoring of haemoglobin and haematocrit. The ferritin level decreased from 5520 to 200 ng/ml after 2 years. The LVEF improved from 18 to 75%. B-type natriuretic peptide (BNP) levels decreased from 1180 to 5.6 pg/ml. A follow-up MRI at 2 years indicated residual iron deposition in the heart. The patient developed complete atrioventricular block and required implantation of a permanent pacemaker at age 28 years.

We first performed direct sequencing on genomic DNA extracts from patient III-3.

3.2. Endomyocardial biopsy
An endomyocardial biopsy from patient III-3 revealed brown pigmented hemosiderin granules in the myocytes. Degeneration of myofilaments was also observed. Electron microscopy showed multiple granular depositions within lysosomes around the perinuclear lesions. These siderin granules consisted of membrane-bound, electron-dense ferritin particles. Degenerative changes such as hyperchromatic nuclei and expanded mitochondria were also visible. The sections used for electron microscopy were too small to evaluate the extent of cardiac fibrosis.

3.3. Detection and identification of mutations and sequencing of the HJV gene
In JH patient III-3, we identified homozygosity for novel C to T transition at nucleotide 934 in exon 4 of the HJV gene. This mutation resulted in an amino acid 312 from glutamine to stop (Q312X) (Fig. 2A).


Figure 02
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  		Fig. 2 (A) HJV Mutation in a JH patient detected by DNA sequencing. Electropherogram shows the exon 4 region of the HJV gene, which contains a homozygous C to T mutated base at nucleotide 934. This mutation results in an amino acid 312 from glutamine to stop (Q312X). The sequence of a normal homozygote (wild type) is also shown. (B) The result of genetic analysis in a family with two JH members. Three individuals (II-2, III-1, III-3) are homozygous for the HJV mutation. Three individuals (II-1, II-3, III-2) are heterozygous for this mutation, and the others are wild type.

 
3.4. Detection and identification of mutations and sequencing of the HAMP, TfR2, ferroportin 1, HFE and ceruloplasmin genes
There were no sequence alterations in the coding or the noncoding regions of the HAMP, TfR2 and ferroportin 1 genes. Similarly, no C282Y H63D mutations in the HFE gene were observed. In the present study, we could not find any sequence alterations in the ceruloplasmin gene.

3.5. Association of HJV gene mutation with JH
The Q312X mutation was examined in the residual 4-generation family and control subjects utilising the allele-specific real-time PCR assay method. The resultant genotype of the family is shown in Fig. 2B. The clinical history of the family revealed no alcohol abuse, blood transfusions or excessive oral iron intake.

Two individuals (II-2, III-1) were homozygous for the Q312X mutation. Subject II-2 is currently 55 years old and has no symptoms of iron overload. She does not fulfil the criteria for JH. Three individuals (II-1, II-3, III-2) were heterozygous for this mutation, and the others were wild type. The abnormal homozygote and heterozygote for the mutation were not found in any of the 361 unrelated control subjects.

Clinical characteristics of the family are shown in Table 2. In subject II-2, an iron loading condition revealed high serum ferritin concentration with an accompanying elevated transferrin iron saturation percentage. LVEF was preserved at 80% in this subject, and plasma BNP levels were 4.5 pg/ml. She was at menopause. Her ferritin levels rose from 390 to 510 ng/ml six months after menopause. In the subjects with heterozygous mutations and wild types, serum ferritin concentration and transferrin iron saturation were in the normal range; however, these levels were relatively high in the subjects that were heterozygotes compared with the normal homozygotes.


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  		Table 2 Clinical features and the results of genetic analysis in the family

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The full length of hemojuvelin consists of 426 amino acids and shows homology to a repulsive guidance molecule (RGM). RGM was first identified as a protein guiding retinal axons to the correct direction during development of the nervous system [17]. Recently, 3 members of RGM have been reported. RGMA and RGMB are mostly expressed in the central nervous system. Hemojuvelin is the third member of RGM and is also called RGMC. The RGM families contain several functional motifs, including an N-terminal signal peptide, a conserved RGD motif, and a partial von Willebrand type D domain and a C-terminal glycosylphosphatidylinositol (GPI)-anchor domain. Hemojuvelin acts as a co-receptor for bone morphogenic protein (BMP). BMP-mediated signalling leads to hepcidin activation in the liver through BMP-activated Smads [18]. Increased iron deposition in the liver, pancreas and heart were shown in a murine model of hemojuvelin deficiency [19,20]. Previous studies suggested that mutant HJV decreased hepcidin gene expression in humans [7]. Hepcidin is a small, cysteine-rich cationic peptide that was first purified from human urine and plasma ultrafiltrate [21,22]. Hepcidin is involved in the down-regulation of intestinal iron absorption and iron release from macrophages [23,24]. The homozygous mutation of the HAMP gene also showed a pure JH phenotype [8]. We found no mutations of the HAMP gene in this family.

Hemojuvelin is present in two forms in vivo. One form of hemojuvelin is retained on the outer face of cell membranes through the addition of GPI anchor domain (m-hemojuvelin). The soluble form of hemojuvelin (s-hemojuvelin) does not contain the GPI anchor. In the biosynthesis of hemojuvelin, autoproteolytic cleavage is an indispensable process for exporting hemojuvelin to the cell surface [25]. Q312X is located downstream of the von Willebrand-like domain. One of the similar truncated variants, R326X, is mainly retained in the endoplasmic reticulum and lacks m-hemojuvelin forms [26]. These truncated variants of HJV maintain the production of s-hemojuvelin. Recently, the reciprocal regulation of hepcidin expression by s-hemojuvelin and m-hemojuvelin was suggested; however, the precise mechanism and action of s-hemojuvelin and m-hemojuvelin remain to be elucidated. The absence of m-hemojuvelin and the presence of s-hemojuvelin possibly play an important role in the progression or regression of Q312X-related haemochromatosis.

The high prevalence of cardiomyopathy and hypogonadism are the most typical findings in JH [5,27]. In one JH patient with cardiomyopathy in this study, cardiac fibrosis was not observed. The pattern of iron deposition in the endomyocardial biopsy did not differ from other patients with HH and secondary haemochromatosis [28,29]. Endomyocardial biopsy is no longer essential for the diagnosis of cardiac haemochromatosis, since the magnetic resonance T2-star technique has been developed for the assessment of tissue iron [30]. Cardiac MRI may be used as an alternative to myocardial biopsy and can be used routinely as a non-invasive method to assess iron deposition. Unfortunately, this sophisticated imaging technique was not available in our institution at the time.

Progressive iron overload associated with HJV mutation is usually observed in the early stages of JH regardless of sex [5]. In the present study, the two affected individuals with a homozygous mutation were in their twenties, and some subjects that were not investigated died at a young age. However, subject II-2 with a homozygous mutation has no symptoms of iron overload. Periodic menstruation in this female subject may have prevented parenchymal iron overload. Recently, the same Q312X mutation was reported in another area of Japan [12]. In that report, the Q312X mutation also caused middle-aged haemochromatosis similar to that in subject II-2. Environmental and/or other genetic factors possibly contribute to the clinical disease progression in HH. Sine we hypothesized that other genetic factors contribute to the progression of JH, we examined possible mutations in the HFE, TfR2, ferroportin 1 and ceruloplasmin genes, but found no mutations in these genes.

JH is a rare disease, and the majority of the HJV gene mutations appear to be private. Haemochromatosis is easily diagnosed by the measurement of transferrin saturation and serum ferritin levels. Early diagnosis is critical for treatment. MRI is a useful and non-invasive method to assess iron deposition. The cardiomyopathy associated with JH is reversible with appropriate therapy.

In conclusion, we identified a Q312X mutation in two patients with JH. This mutation appears to predispose Japanese individuals to severe cardiomyopathy.


   Acknowledgements
 
We are grateful to Dr. Masayoshi Kage, Department of Pathology, Kurume University School of Medicine and Dr. Takahisa Yoshida, section of pathology, Fukuoka Tokusyukai Hospital for their important contributions. The cooperation of patients and families involved in this study is gratefully acknowledged. This study was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture in Japan.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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