Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Orphanet J Rare Dis. 2024 Nov 19;19(1):429. doi: 10.1186/s13023-024-03439-9.
Hereditary hemochromatosis (HH) is an iron overload disorder and can be caused by variants in non-HFE genes in Chinese patients. However, there is still a considerable proportion of patients suffering from unexplained iron overload. In our previous study, we had identified the p.R269Q variant in exon 4 of the Bone morphogenetic protein 4 (BMP4) gene in Chinese patients with unexplained primary iron overload by Whole Exome sequencing, and then the BMP4 p.H251Y variant was identified by Sanger sequencing in a Chinese patient with secondary iron overload. Our study aimed to explore the pathogenicity and underlying mechanism of BMP4 p.H251Y and BMP4 p.R269Q variants in patients with iron overload.
Sanger sequencing was conducted to identify the novel variants in the BMP4 gene of patients with unexplained iron overload. MRI and liver biopsy were used to display iron overload in the liver of the patient harboring the BMP4 p.H251Y variant. The BMP4 and hepcidin levels in BMP4 knockdown and BMP4 variant cells were examined by enzyme-linked immunosorbent assay. The effects of BMP4 p.H251Y and BMP4 p.R269Q variants on the hepcidin-regulation pathway were studied.
One of 54 HH patients (1.85%) harbored the BMP4 p.R269Q variant. One of 148 patients (0.68%) with secondary hemochromatosis harbored the BMP4 p.H251Y variant, and these two variants were not found in 100 Chinese general population. For the patient harboring the BMP4 p.H251Y variant, abdominal MRI and Perl's staining of liver tissue displayed iron overload in the liver. Cells transfected with the BMP4 p.H251Y and p.R269Q variants showed down-regulation of hepcidin level and BMP/SMAD pathway compared with cells transfected with the wild-type BMP4 vector.
The BMP4 p.H251Y and p.R269Q variants can downregulate hepcidin levels by inhibiting the BMP/SMAD axis, suggesting they may play pathogenic roles in iron overload.
遗传性血色素沉着症（HH）是一种铁过载疾病，在中国患者中可以由非 HFE 基因的变异引起。然而，仍有相当一部分不明原因铁过载的患者。在我们之前的研究中，通过全外显子组测序，我们在不明原因原发性铁过载的中国患者中发现了骨形态发生蛋白 4（BMP4）基因外显子 4 中的 p.R269Q 变异，然后通过 Sanger 测序在中国 1 例继发性铁过载患者中发现了 BMP4 p.H251Y 变异。我们的研究旨在探讨 BMP4 p.H251Y 和 BMP4 p.R269Q 变异在铁过载患者中的致病性和潜在机制。
对不明原因铁过载患者的 BMP4 基因进行 Sanger 测序，以确定新的变异。对携带 BMP4 p.H251Y 变异的患者进行 MRI 和肝活检，以显示肝脏铁过载。通过酶联免疫吸附试验检测 BMP4 敲低和 BMP4 变异细胞中的 BMP4 和铁调素水平。研究 BMP4 p.H251Y 和 BMP4 p.R269Q 变异对铁调素调节途径的影响。
54 例 HH 患者中有 1 例（1.85%）携带 BMP4 p.R269Q 变异，148 例继发性血色素沉着症患者中有 1 例（0.68%）携带 BMP4 p.H251Y 变异，而这两种变异在 100 名中国普通人群中均未发现。对于携带 BMP4 p.H251Y 变异的患者，腹部 MRI 和肝脏组织 Perl 染色显示肝脏铁过载。与转染野生型 BMP4 载体的细胞相比，转染 BMP4 p.H251Y 和 p.R269Q 变异体的细胞铁调素水平和 BMP/SMAD 通路下调。
BMP4 p.H251Y 和 p.R269Q 变异可通过抑制 BMP/SMAD 轴下调铁调素水平，提示其可能在铁过载中发挥致病作用。
