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• W2021486543 abstract "The congenital dyserythropoietic anaemias (CDAs) are a heterogeneous group of genetic disorders of red cell production characterized by ineffective erythropoiesis and dyserythropoiesis. Three major types of CDA have been determined on the basis of morphological findings and genetic variations, and are designated as CDA types I, II and III (Wickramasinghe & Wood, 2005). To date, around 500 cases of CDA have been reported worldwide and CDA II accounts for nearly two-thirds of these (Kamiya & Manabe, 2010). CDA II is a rare autosomal recessive disorder with major clinical manifestations of mild to transfusion-demanding haemolytic anaemia, fatigue, jaundice and hepatosplenomegaly. Bone marrow examination always reveals marked erythroid hyperplasia with 10–35% of late erythroblasts being binucleated or multinucleated (Wickramasinghe & Wood, 2005). The ineffective erythropoiesis that is associated with CDA frequently leads to increased dietary iron absorption and tissue iron loading. Cholelithiasis is another complication frequently associated with CDA II (Hermann et al, 2003). Although the clinical presentation of CDA II has been extensively studied, it was not until 2009 that SEC23B, the gene encoding the secretory COPII component SEC23B, was identified as the mutated gene in this disease (Schwarz et al, 2009). Since then, over 50 pathogenic mutations have been reported in CDA II patients of different origin (according to the Human Gene Mutation Database, HGMD®, http://www.hgmd.org). However, to the best of our knowledge, mutations underlying CDA II in East Asian patients have yet to be described. We here report two novel pathogenic mutations in SEC23B in a Chinese CDA II patient and his direct relatives. Interestingly, some members of this family also carried a novel missense mutation in the HFE2 gene, which encodes hemochromatosis type 2 (juvenile) (HFE2), also known as haemojuvelin (HJV), an upstream modulator of the iron regulatory hormone hepcidin. The proband, 50-year-old male, presented with chronic fatigue and dark urine. Chronic haemolysis was suspected based on typical clinical manifestations of marked splenomegaly and early onset intermittent jaundice (at age < 12 years). Laboratory tests showed anaemia (haemoglobin 95 g/l; normal range 120–160 g/l for males) with increased mean corpuscular volume (MCV) (107·3 fl; normal range 82·0–97·0 fl) and a suboptimal reticulocyte response (1·72%; normal range 0·80–2·00%). Iron overload was suggested by elevated transferrin saturation (TS) and serum ferritin (SF) concentrations (Table 1). Liver biopsy revealed increased hepatic parenchymal cell stainable iron in a periportal distribution. The causes of iron loading anaemia were investigated. Glucose-6-phosphate dehydrogenase and pyruvate kinase activities were normal, excluding deficiencies in either of these enzymes. Thalassaemia, atransferrinaemia and acaeruloplasminaemia also seemed unlikely based on the patient's increased MCV. Examination of peripheral and bone marrow blood smears suggested a diagnosis of CDA. In order to confirm this, we directly sequenced the CDAN1 and SEC23B genes, which are responsible for CDA I and CDA II, respectively, of this patient and his direct relatives with the corresponding primers (Table SI) (Kamiya & Manabe, 2010). As the patient also showed significant iron overload (a feature not associated with CDA III, which is why CDA III was excluded as a diagnosis), we also sequenced the major genes that predispose to haemochromatosis when mutated (HFE, TFR2, HAMP, HFE2 and SLC40A1) of the proband and his direct relatives. Two novel mutations were found in the patient's SEC23B gene while no mutation was detected in his CDAN1 gene or haemochromatosis genes. The c. 71 G>A mutation (Fig 1; Fig S1A) in SEC23B results in a premature stop codon (W24X) in the N-terminus of the protein. Thus, the SEC23B encoded by this allele has lost most of its essential functional domains (zinc finger, trunk, beta sheet, helical and gelsolin domains) (Schwarz et al, 2009). The c. 74 C>A transversion (Fig 1; Fig S1A) causes a P25H substitution in the SEC23B protein. Proline plays a pivotal role in the formation of essential secondary structures (alpha helices and beta sheets). Furthermore, the proline residue at position 25 is highly conserved among SEC23B proteins from several mammalian species (Fig S2A). Therefore, we speculate that the P25H substitution, although not located within functional domains, will severely affect the biochemical properties of the SEC23B protein. Of the patient's direct relatives, one carried a heterozygous P25H mutation in their SEC23B gene but had no haematological abnormality (data not shown) or iron overload (Table 1). No other SEC23B mutations were detected. The serum hepcidin level of the proband was below the detection limit of the assay (<1 nM), using a previously described method (Bansal et al, 2009). This is consistent with iron overload and with previous work that suggested growth differentiation factor 15 contributes to the inappropriate suppression of hepcidin in CDA II patients (Casanovas et al, 2011). In addition to mutations in the SEC23B gene, a heterozygous c. 55A>G mutation in the HFE2 gene was found in some family members (Fig 1; Fig S1B) when their genomic DNA samples were amplified with corresponding primers (Table SII). This mutation leads to the T19A substitution in the HFE2 protein and corresponds to a putative signalling peptide region that is highly conserved among mammalian species (Fig S2B) (Huang et al, 2004). We investigated whether the HFE2 mutation was associated with altered serum hepcidin levels and iron indices of the carriers in this family, but no consistent association was found (Table 1). Serum hepcidin levels of female HFE2 mutation carriers in this family were below the detection limit (<1 nM), while the hepcidin level of the male HFE2 mutation carrier was within normal range. Although all subjects had high normal to slightly elevated transferrin saturation levels, they were not iron overloaded (Table 1). Heterozygosity for HFE2 mutations is not usually associated with iron loading, but one study reported a 49-year-old male with a heterozygous missense mutation (c. 842T>C; I281T) and elevated serum ferritin concentration. However, no direct genotype-phenotype correlation was suggested (Huang et al, 2004). Thus, we speculate that the T19A substitution is only a modifying factor on the normal iron homeostasis of mutation carriers in this family and it may not have a significant effect on the function of HFE2. This work was supported by grants from MOST 973 (2012CB934000) and NSFC (10979011, 30900278). G.N. gratefully acknowledges the support of Chinese Academy of Sciences Hundred Talents Programme. GJA is the recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia. The authors thank Professor Clara Camaschella for careful reading of the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2021486543 title "A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively" @default.
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