Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1.
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.
Dgany
Orly
O
Pediatric Hematology Laboratory, Felsenstein Research Center, Rabin Medical Center, Petah Tikva, Israel.
Avidan
Nili
N
Delaunay
Jean
J
Krasnov
Tatyana
T
Shalmon
Lea
L
Shalev
Hanna
H
Eidelitz-Markus
Tal
T
Kapelushnik
Joseph
J
Cattan
Daniel
D
Pariente
Alexandre
A
Tulliez
Michel
M
Crétien
Aurore
A
Schischmanoff
Pierre-Olivier
PO
Iolascon
Achille
A
Fibach
Eithan
E
Koren
Ariel
A
Rössler
Jochen
J
Le Merrer
Martine
M
Yaniv
Isaac
I
Zaizov
Rina
R
Ben-Asher
Edna
E
Olender
Tsvyia
T
Lancet
Doron
D
Beckmann
Jacques S
JS
Tamary
Hannah
H
D000595:Amino Acid Sequence; D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics*; D001483:Base Sequence; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003241:Consanguinity; D004920:Erythropoiesis; D005091:Exons / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007557:Israel; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
C470477:CDAN1 protein, human; D006023:Glycoproteins; D009687:Nuclear Proteins; D012333:RNA, Messenger