Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1
Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1
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DOI：
10.1086/344781
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发表时间：
2002-12-01
影响因子：
9.8
通讯作者：
Tamary, H
中科院分区：
文献类型：
--
作者：
Dgany, O;Avidan, N;Tamary, H
先天性红细胞生成不良性贫血（CDAs）是一组罕见的遗传性红细胞疾病，与晚期红细胞前体细胞发育异常有关。CDA I型（CDAI [MIM 224120]，基因符号CDAN 1）的特征在于红细胞病理学特征，如核间染色质桥、海绵状异染色质和核膜内陷，将细胞质细胞器带入细胞核。45个具有CDAI的高度近交的以色列贝都因人的簇使得能够将CDAN 1疾病基因定位到2 Mb间隔，现在精确到1.2 Mb，包含人类染色体15 q15上的15个候选基因（Tamary等人，1998）。在对这些基因中的13个进行表征和排除后，我们通过9个CDAI家族中的12个不同突变鉴定了CDAN 1基因。这个28个外显子的基因，这是普遍转录成4738 nt的mRNA，基因预测和同源性搜索的基础上重建。它编码codanin-1，一种假定的1，226个氨基酸的O-糖基化蛋白，没有明显的跨膜结构域。Codanin-1有一个150个氨基酸残基的氨基末端结构域，与胶原蛋白序列相似，还有两个较短的片段，与微管相关蛋白MAP 1B（神经轴蛋白）和突触蛋白相似性较弱。这些发现和细胞表型表明，codanin-1可能参与核膜的完整性，可以想象与微管附着。codanin-1作为正常红细胞生成的基础的具体机制仍有待阐明。
Congenital dyserythropoietic anemias (CDAs) constitute a rare group of inherited red-blood-cell disorders associated with dysplastic changes in late erythroid precursors. CDA type I (CDAI [MIM 224120], gene symbol CDAN1) is characterized by erythroid pathological features such as internuclear chromatin bridges, spongy heterochromatin, and invagination of the nuclear membrane, carrying cytoplasmic organelles into the nucleus. A cluster of 45 highly inbred Israeli Bedouin with CDAI enabled the mapping of the CDAN1 disease gene to a 2-Mb interval, now refined to 1.2 Mb, containing 15 candidate genes on human chromosome 15q15 (Tamary et al. 1998). After the characterization and exclusion of 13 of these genes, we identified the CDAN1 gene through 12 different mutations in 9 families with CDAI. This 28-exon gene, which is transcribed ubiquitously into 4738 nt mRNA, was reconstructed on the basis of gene prediction and homology searches. It encodes codanin-1, a putative o-glycosylated protein of 1,226 amino acids, with no obvious transmembrane domains. Codanin-1 has a 150-residue amino-terminal domain with sequence similarity to collagens and two shorter segments that show weak similarities to the microtubule-associated proteins, MAP1B (neuraxin) and synapsin. These findings, and the cellular phenotype, suggest that codanin-1 may be involved in nuclear envelope integrity, conceivably related to microtubule attachments. The specific mechanisms by which codanin-1 underlies normal erythropoiesis remain to be elucidated.