Hereditary hyperferritinemia-cataract syndrome: Relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA
Hereditary hyperferritinemia-cataract syndrome: Relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA
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DOI：
10.1182/blood.v90.2.814.814_814_821
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发表时间：
1997-07-15
期刊：
影响因子：
20.3
通讯作者：
Arosio, P
中科院分区：
文献类型：
--
作者：
Cazzola, M;Bergamaschi, G;Arosio, P
最近的报道描述了一个家族，其中血清铁蛋白升高与铁过载无关，先天性核性白内障作为常染色体显性遗传。我们研究了两个家族的高铁蛋白血症的分子发病机制，这两个家族表现出这种新的遗传性疾病的不同表型表达。家族1的患病个体的血清铁蛋白水平为950 - 1，890 μ g/L，家族2的患病个体的血清铁蛋白水平为366 - 635 μ g/L。通过使用特异性的H和L铁蛋白亚基的单克隆抗体，血清铁蛋白被发现基本上是L型在正常和受影响的个人。后者也显示了正常量的H-型铁蛋白在循环单核细胞;相反，L-型铁蛋白含量是正常的13倍，在家庭1和5倍正常的家庭2平均。血清铁蛋白糖基化在正常和受影响的个人。单核细胞L型铁蛋白含量与血清铁蛋白浓度呈显著正相关（r = 0.95，P <0.00001），提示细胞内铁蛋白的过量产生是高铁蛋白血症的直接原因。发现L亚基合成失调是由基因组L亚基DNA的非编码序列中的不同点突变引起的，其表现为称为铁调节元件（IRE）的mRNA顺式作用元件。来自家族1的受影响个体对于形成IRE凸起的高度保守的三核苷酸基序中的点突变（单个G至A改变）是杂合的。来自家族2的受影响成员是IRE下茎中双点突变的杂合型。使用凝胶阻滞试验，观察到的分子病变显示可显著降低IRE对铁调节蛋白（IRP）的亲和力，IRP抑制铁蛋白mRNA翻译。高铁蛋白血症的程度与白内障的严重程度之间的直接关系表明，后者是透镜纤维内过量铁蛋白产生的结果。这些发现提供了强有力的证据，证明血清铁蛋白是细胞内铁蛋白合成的副产物，并且19号染色体上的L亚基基因是糖基化血清铁蛋白的来源。当临床医生面对一个表面上健康的人的高血清铁蛋白时，这种新的遗传性疾病应该被考虑在内。(C)1997年，美国血液学会。
Recent reports have described families in whom a combination of elevated serum ferritin not related to iron overload and congenital nuclear cataract is transmitted as an autosomal dominant trait. We have studied the molecular pathogenesis of hyperferritinemia in two families showing different phenotypic expression of this new genetic disorder, Serum ferritin levels ranged from 950 to 1,890 mu g/L in affected individuals from family 1, and from 366 to 635 mu g/L in those from family 2, Cataract was clinically manifested in family 1 and asymptomatic in family 2. By using monoclonal antibodies specific for the H and L ferritin subunits, serum ferritin was found to be essentially L type in both normal and affected individuals. The latter also showed normal amounts of H-type ferritin in circulating mononuclear cells; on the contrary, L-type ferritin contents were 13 times normal in family 1 and five times normal in family 2 on average. Serum ferritin was glycosylated in both normal and affected individuals. There was a close relationship between mononuclear cell L-type ferritin content and serum ferritin concentration (r = 0.95, P < .00001), suggesting that the excess production of ferritin in cells was directly responsible for the hyperferritinemia. The dysregulated L-subunit synthesis was found to result from different point mutations in a non-coding sequence of genomic L-subunit DNA, which behaves as an mRNA cis-acting element known as iron regulatory element (IRE), Affected individuals from family 1 were heterozygous for a point mutation (a single G to A change) in the highly conserved, three-nucleotide motif forming the IRE bulge. Affected members from family 2 were heterozygous for a double point mutation in the IRE lower stem, Using a gel retardation assay, the observed molecular lesions were shown to variably reduce the IRE affinity for an iron regulatory protein (IRP), which inhibits ferritin mRNA translation. The direct relationship between the degree of hyperferritinemia and severity of cataract suggests that this latter is the consequence of excessive ferritin production within the lens fibers, These findings provide strong evidence that serum ferritin is a byproduct of intracellular ferritin synthesis and that the L-subunit gene on chromosome 19 is the source of glycosylated serum ferritin, From a practical standpoint, this new genetic disorder should be taken into account by clinicians when facing a high serum ferritin in an apparently healthy person. (C) 1997 by The American Society of Hematology.