Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1

Orly Dgany, Nili Avidan, Jean Delaunay, Tatyana Krasnov, Lea Shalmon, Hanna Shalev, Tal Eidelitz-Markus, Joseph Kapelushnik, Daniel Cattan, Alexandre Pariente, Michel Tulliez, Aurore Crétien, Pierre Olivier Schischmanoff, Achille Iolascon, Eithan Fibach, Ariel Koren, Jochen Rössler, Martine Le Merrer, Isaac Yaniv, Rina ZaizovEdna Ben-Asher, Tsvyia Olender, Doron Lancet, Jacques S. Beckmann, Hannah Tamary

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1467-1474
Number of pages8
JournalAmerican Journal of Human Genetics
Volume71
Issue number6
DOIs
StatePublished - 1 Dec 2002

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