背景:血色病是一种遗传性疾病,其特征是铁在各种组织和器官中的过度沉积,最终导致器官损伤,包括肝硬化,糖尿病,心肌病,等。SLC40A1相关的血色素沉着症与SLC40A1基因的功能获得突变有关,编码铁转运蛋白。虽然中国大陆有零星的这种情况的报道,对与SLC40A1p.Y333H突变相关的表型和遗传模式的理解仍不完全.
方法:我们报告了一个中国汉族人群p.Y333H杂合突变的家系。先证者是一名64岁的男性,抱怨肝酶水平持续异常1年,有膝关节疼痛史,糖尿病和皮肤色素沉着。他显示血清铁蛋白水平和转铁蛋白饱和度显着升高。磁共振成像显示肝脏中铁沉积,脾,脾还有胰腺,伴随着肝硬化和脾肿大。全外显子组测序鉴定出杂合等位基因变体c.997T>C(p。Y333H)。家庭成员的遗传筛查确定了四个一级亲属和三个二级亲属具有相同的突变。包括来自两项已发表研究的具有这种突变的其他病例。在先证者和经过筛选的亲属中,所有8名年龄在30岁以上的男性的铁蛋白水平>1000微克/升,转铁蛋白饱和度>90%。本研究中有4例器官损伤患者接受了治疗性静脉切开术,减轻临床症状,改善转铁蛋白饱和度和血清铁蛋白。
结论:本研究报告了迄今为止中国人群中最大的具有杂合SLC40A1p.Y333H突变的谱系。在中国家庭中,30岁以上的男性因SLC40A1p.Y333H突变而导致血色素沉着症,表现出严重的铁超负荷表型。
BACKGROUND: Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete.
METHODS: We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin.
CONCLUSIONS: This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.