Alternative titles; symbols
HGNC Approved Gene Symbol: CDAN1
Cytogenetic location: 15q15.2 Genomic coordinates (GRCh38) : 15:42,723,544-42,737,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.2 | Dyserythropoietic anemia, congenital, type Ia | 224120 | Autosomal recessive | 3 |
Congenital dyserythropoietic anemias (CDAs) constitute a rare group of inherited red blood cell disorders associated with dysplastic changes in late erythroid precursors. A cluster of 45 highly inbred Israeli Bedouin permitted Tamary et al. (1998) to map the gene for CDA type Ia (224120) to a 2-Mb interval on chromosome 15q15. Dgany et al. (2002) refined the localization to a 1.2-Mb interval and identified CDAN1, the gene responsible for CDA type Ia, through the identification of mutations in 9 families with the disorder. The CDAN1 gene product, codanin-1, is a putative O-glycosylated protein of 1,226 amino acids with no obvious transmembrane domains. Codanin-1 has a 150-residue N-terminal domain with sequence similarity to collagens, as well as 2 shorter segments that show weak similarities to the microtubule-associated proteins MAP1B (157129) and synapsin (SYN1; 313440). Alternative splicing produces a variant encoding a 1,103-amino acid isoform. Northern blot analysis detected a 4.7-kb CDAN1 transcript in all 8 tissues tested. Based on their findings and the cellular phenotype of CDA type Ia, Dgany et al. (2002) suggested that codanin-1 may be involved in nuclear envelope integrity, conceivably related to microtubule attachments.
Using several techniques, including sequencing clones that rescued the discs lost (dlt) phenotype in Drosophila, Pielage et al. (2003) determined that CDAN1 is the human homolog of dlt. They showed that dlt is an evolutionarily conserved protein required for cell survival and cell cycle progression in the fly.
Dgany et al. (2002) determined that the CDAN1 gene contains 28 exons and spans 15 kb.
Dgany et al. (2002) mapped the CDAN1 gene to chromosome 15q15.
Dgany et al. (2002) identified 12 different mutations in the CDAN1 gene in 9 families with congenital dyserythropoietic anemia type Ia (CDAN1A; 224120).
In 1 French family in which a 56-year-old male and his 2 brothers suffered from CDA type I, asthenoteratozoospermia, and nonsyndromic deafness, Dgany et al. (2002) identified a point mutation within the codanin gene (N598S; 607465.0003) as the cause of CDA type Ia. Avidan et al. (2003) found that these 3 sibs were also homozygous for an approximately 70-kb deletion in chromosome 15q15, which removed the entire stereocilin gene (STRC; 606440) and truncated the CATSPER2 gene (607249). Avidan et al. (2003) suggested that lack of functional stereocilin, which is mutated in nonsyndromic sensorineural deafness (DFNB16; 603720), and CATSPER2, a voltage-gated cation channel expressed exclusively in spermatozoa, may explain the observed deafness and male infertility phenotypes, respectively.
In studies of 8 unrelated patients with sporadic CDA type I, 3 of whom had complex bone disease, Tamary et al. (2005) identified 6 different mutations in the CDAN1 gene. In 2 patients, only 1 mutation was identified, and in 1 patient, no CDAN1 mutation was identified. No patient was homozygous for a null-type mutation. However, 1 patient with complex bone disease was homozygous for a splice site mutation, IVS12+5G-A (607465.0006). Western blotting revealed that codanin-1 synthesis was 65% less than the control in this patient. Although the absence of codanin-1 is probably lethal, the presence of 35% of the protein was compatible with life but was associated with severe clinical manifestations. No correlation could be established between the expected levels of codanin-1 or the nature of the mutation and the severity of the clinical manifestations.
In 15 of 16 CDA I patients analyzed, Heimpel et al. (2006) identified 17 different mutations in at least 1 allele of the CDAN1 gene. All but 1 of the mutations were located in exons 12 to 28; 1 mutation was found in exon 6.
In Israeli Bedouin patients with type Ia congenital erythropoietic anemia (CDAN1A; 224120), Dgany et al. (2002) identified a homozygous C-to-T transition at nucleotide 3238 in the CDAN1 gene, causing an arg1040-to-trp substitution.
In a French Polynesian family with type Ia congenital dyserythropoietic anemia (CDAN1A; 224120), Dgany et al. (2002) identified a C-to-T transition at nucleotide 3503 in the CDAN1 gene, resulting in a pro1129-to-leu substitution.
In a French family with type Ia congenital dyserythropoietic anemia (CDAN1A; 224120), Dgany et al. (2002) identified homozygosity for an A-to-G transition at nucleotide 1910 in the CDAN1 gene, resulting in an asn598-to-ser substitution. The 3 sibs who were affected also exhibited sensorineural deafness and a lack of motile sperm cells. These symptoms could be accounted for by a large 70-kb deletion 1 Mb distal to the CDAN1 gene. Thus, it appeared to be a case of tightly linked independent mutations on the same haplotype representing a contiguous gene syndrome.
Avidan et al. (2003) determined that the 70-kb deletion removed the entire stereocilin gene (STRC; 606440) and truncated the CATSPER2 gene (607249). They suggested that lack of functional stereocilin, which is mutated in nonsyndromic sensorineural deafness (DFNB16; 603720), and CATSPER2, a voltage-gated cation channel expressed exclusively in spermatozoa, may explain the observed deafness and male infertility phenotypes, respectively, in this family.
In a European family, Dgany et al. (2002) identified individuals with type Ia congenital dyserythropoietic anemia (CDAN1A; 224120) who were compound heterozygotes for 2 missense mutations in the CDAN1 gene: a C-to-T transition at nucleotide 2129, resulting an a pro671-to-leu substitution, and a T-to-A transversion at nucleotide 2716, resulting in a phe866-to-ile substitution (607465.0005). The mutations occurred in exons 14 and 19, respectively.
For discussion of the T-to-A transversion at nucleotide 2716 in the CDAN1 gene, resulting in a phe866-to-ile (F866I) substitution, that was found in compound heterozygous state in a patient with congenital dyserythropoietic anemia type Ia (CDAN1A; 224120) by Dgany et al. (2002), see 607465.0004.
In an Israeli Arab patient with type Ia congenital dyserythropoietic anemia (CDAN1A; 224120), Tamary et al. (2005) identified homozygosity for a G-to-A transition at the +5 consensus site position in intron 12 (IVS12+5G-A) of the CDAN1 gene. Sequence analysis of exons 11 to 15 revealed an expected 659-bp transcript and an 898-bp transcript that retained intron 12 (139 bp). A 65% decrease in codanin-1 synthesis was estimated. The patient showed dysmorphism of the left foot.
Ahmed et al. (2006) described a 3-bp in-frame deletion in the CDAN1 gene, resulting in deletion of valine-3721, as the basis of a sporadic case of type Ia congenital dyserythropoietic anemia (CDAN1A; 224120).
Ahmed, M. R., Chehal, A., Zahed, L., Taher, A., Haidar, J., Shamseddine, A., O'Hea, A.-M., Bienz, N., Dgany, O., Avidan, N., Beckmann, J. S., Tamary, H., Higgs, D., Vyas, P., Wood, W. G., Wickramasinghe, S. N. Linkage and mutational analysis of the CDAN1 gene reveals genetic heterogeneity in congenital dyserythropoietic anemia type I. (Letter) Blood 107: 4968-4969, 2006. [PubMed: 16754775] [Full Text: https://doi.org/10.1182/blood-2006-01-0081]
Avidan, N., Tamary, H., Dgany, O., Cattan, D., Pariente, A., Thulliez, M., Borot, N., Moati, L., Barthelme, A., Shalmon, L., Krasnov, T., Ben-Asher, E., and 9 others. CATSPER2, a human autosomal nonsyndromic male infertility gene. Europ. J. Hum. Genet. 11: 497-502, 2003. [PubMed: 12825070] [Full Text: https://doi.org/10.1038/sj.ejhg.5200991]
Dgany, O., Avidan, N., Delaunay, J., Krasnov, T., Shalmon, L., Shalev, H., Eidelitz-Markus, T., Kapelushnik, J., Cattan, D., Pariente, A., Tulliez, M., Cretien, A., and 13 others. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am. J. Hum. Genet. 71: 1467-1474, 2002. [PubMed: 12434312] [Full Text: https://doi.org/10.1086/344781]
Heimpel, H., Schwarz, K., Ebnother, M., Goede, J. S., Heydrich, D., Kamp, T., Plaumann, L., Rath, B., Roessler, J., Schildknecht, O., Schmid, M., Wuillemin, W., Einsiedler, B., Leichtle, R., Tamary, H., Kohne, E. Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation. Blood 107: 334-340, 2006. [PubMed: 16141353] [Full Text: https://doi.org/10.1182/blood-2005-01-0421]
Pielage, J., Stork, T., Bunse, I., Klambt, C. The Drosophila cell survival gene discs lost encodes a cytoplasmic codanin-1-like protein, not a homolog of tight junction PDZ protein Patj. Dev. Cell 5: 841-851, 2003. [PubMed: 14667407] [Full Text: https://doi.org/10.1016/s1534-5807(03)00358-7]
Tamary, H., Dgany, O., Proust, A., Krasnov, T., Avidan, N., Eidelitz-Markus, T., Tchernia, G., Genevieve, D., Cormier-Daire, V., Bader-Meunier, B., Ferrero-Vacher, C., Munzer, M., Gruppo, R., Fibach, E., Konen, O., Yaniv, I., Delaunay, J. Clinical and molecular variability in congenital dyserythropoietic anaemia type I. Brit. J. Haemat. 130: 628-634, 2005. [PubMed: 16098079] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05642.x]
Tamary, H., Shalmon, L., Shalev, H., Halil, A., Dobrushin, D., Ashkenazi, N., Zoldan, M., Resnitzky, P., Korostishevsky, M., Bonne-Tamir, B., Zaizov, R. Localization of the gene for congenital dyserythropoietic anemia type I to a less than 1-cM interval on chromosome 15q15.1-15.3. Am. J. Hum. Genet. 62: 1062-1069, 1998. [PubMed: 9545404] [Full Text: https://doi.org/10.1086/301834]