Congenital Dyserythropoietic Anemia Type I Is Caused by Mutations in Codanin-1

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.

CATSPER2, a human autosomal nonsyndromic male infertility gene

“…Although no consanguinity was reported, the affected brothers were homozygous for the same N598S CDAI mutation 14 as well as for a battery of chromosome 15q markers (Figure 1a), which is suggestive of an unsuspected consanguineous antecedent. Marker D15S784 failed, however, to be amplified with several sets of primers, suggesting the existence of a possible deletion in these patients, which could account for their unique syndromic phenotype.…”

“…In the course of positional cloning of the Congenital Dyserythropoietic Anemia type I (CDAI) gene [MIM 224120], 14 which was previously localized to chromosome 15q15.1 -15.3, 15 we examined a family of French origin, in which the clinical and hematological features of the propositus (II-2, Figure 1a) and of his two affected brothers were compatible with CDAI (Table 1). However, unlike other CDAI patients, the brothers suffered also from sensorineural deafness, and a severe reduction in the percentage of motile spermatozoa in their ejaculates ( Table 1).…”

Congenital Dyserythropoietic Anemia Type 1: Report of One Patient and Analysis of Previously Reported Patients Treated with Interferon Alpha

“…Light and electron microscopy findings of the bone marrow erythroblasts, the gold standard for CDA type 1 determination [4] were consistent with the diagnosis. The causative gene mutation for CDA type 1 (Codanin-1 mutation) was described first in 2002 [10]. So far, approximately 30 CDAN1 mutations have been reported in CDA type 1 patients.…”

Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1α localization in erythroblasts

“…Most cases of CDA-1, a hereditary anemia characterized by erythroblasts with abnormal chromatin structure, result from mutations in CDAN1. 3 The ultrastructural phenotype in CDA-1 calls for an investigation of proteins involved in the higher-order structure of chromatin, and of potential consequences on gene regulation in mutants. Surprisingly, no studies of overall chromatin structure analyses in CDA patients have been reported in the literature.…”