Alternative titles; symbols
HGNC Approved Gene Symbol: ANKRD26
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38) : 10:26,947,582-27,100,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.1 | Thrombocytopenia 2 | 188000 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned ANKRD26, which they designated KIAA1074. The deduced protein contains 1,709 amino acids. RT-PCR ELISA detected moderate expression in fetal liver and in nearly all adult tissues and specific brain regions examined. Low expression was detected in adult pancreas and spleen and in fetal brain.
By database analysis, Hahn et al. (2006) identified ANKRD26 as a distant homolog of the POTE family (see POTE2; 608914). The ANKRD26 protein contains 4 N-terminal ankyrin repeats and a C-terminal coiled-coil region. It shares 61.2% amino acid identity with mouse Ankrd26.
Hahn et al. (2006) determined that the ANKRD26 gene contains 34 exons.
Using radiation hybrid analysis, Kikuno et al. (1999) mapped the ANKRD26 gene to chromosome 10. By genomic sequence analysis, Hahn et al. (2006) mapped the ANKRD26 gene to chromosome 10p12.1. They mapped the mouse Ankrd26 gene to chromosome 6F1.
In 9 of 20 unrelated families with autosomal dominant nonsyndromic thrombocytopenia-2 (THC2; 188000), Pippucci et al. (2011) identified 6 different heterozygous mutations in the 5-prime promoter region of the ANKRD26 gene (see, e.g., 610855.0001-610855.0003). All of the mutations occurred in a highly conserved 19-nucleotide stretch. In vitro functional expression assays in Dami human megakaryoblastic cells indicated that the mutations resulted in increased expression, particularly when the cells were stimulated toward maturation. The findings suggested a gain-of-function effect. Pippucci et al. (2011) speculated that the ANKRD26 mutations interfere with the mechanism controlling the expression of ANKRD26, which would then affect megakaryopoiesis and platelet production, perhaps by inducing apoptosis. The phenotype was characterized by thrombocytopenia without any morphologic or functional platelet defect.
Bera et al. (2008) generated mice homozygous for partial inactivation of the Ankrd26 gene and observed the development of extreme obesity, insulin resistance, and a dramatic increase in body size. The obesity was associated with hyperphagia with no reduction in energy expenditure or activity. Bera et al. (2008) detected expression of Ankrd26 in the arcuate and ventromedial nuclei within the hypothalamus and in the ependyma and the circumventricular organs that act as an interface between the peripheral circulation and the brain. They also found increased phosphorylation of Akt (see AKT1; 164730) and mTOR (FRAP1; 601231) in mutant hearts compared to wildtype.
In 7 affected members of a large Italian family with autosomal dominant thrombocytopenia-2 (THC2; 188000) originally reported by Savoia et al. (1999), Pippucci et al. (2011) identified a heterozygous -134G-A transition in the 5-prime promoter region of the ANKRD26 gene. The same mutation was also identified in 2 members of a second Italian family with the disorder. The mutation was not found in 500 controls. In vitro functional expression studies of the mutant protein in K562 undifferentiated myeloid cells showed 2.7 to 4.5-fold increased expression of a luciferase reporter. Transfection of the -134G-A mutation in Dami human megakaryoblastic cells showed overexpression of the reporter gene in cells that were both unstimulated and stimulated toward megakaryocytic maturation. Punzo et al. (2010) determined that this large Italian family, originally reported by Savoia et al. (1999), had a pathogenic mutation in the ACBD5 gene (616618) that caused the disorder, but the findings of Pippucci et al. (2011) suggested that the ANKRD26 mutation was responsible for the phenotype.
In 6 affected members of a large Italian family with autosomal dominant thrombocytopenia-2 (THC2; 188000), Pippucci et al. (2011) identified a heterozygous -127A-T transversion in the 5-prime promoter region of the ANKRD26 gene. The same mutation was also identified in 2 members of family from Argentina with the disorder. The mutation was not found in 500 controls. Transfection of the -127A-T mutation in Dami human megakaryoblastic cells showed overexpression of the reporter gene in Dami cells that were stimulated toward megakaryocytic maturation, but not in unstimulated cells.
In 7 affected members of a large Italian family with autosomal dominant thrombocytopenia-2 (THC2; 188000), Pippucci et al. (2011) identified a heterozygous -128G-A transition in the 5-prime promoter region of the ANKRD26 gene. The same mutation was also identified in 3 members of another Italian family with the disorder. The mutation was not found in 500 controls. Transfection of the -128G-A mutation in Dami human megakaryoblastic cells showed overexpression of the reporter gene in cells that were both unstimulated and stimulated toward megakaryocytic maturation.
Bera, T. K., Liu, X.-F., Yamada, M., Gavrilova, O., Mezey, E., Tessarollo, L., Anver, M., Hahn, Y., Lee, B., Pastan, I. A model for obesity and gigantism due to disruption of the Ankrd26 gene. Proc. Nat. Acad. Sci. 105: 270-275, 2008. [PubMed: 18162531] [Full Text: https://doi.org/10.1073/pnas.0710978105]
Hahn, Y., Bera, T. K., Pastan, I. H., Lee, B. Duplication and extensive remodeling shaped POTE family genes encoding proteins containing ankyrin repeat and coiled coil domains. Gene 366: 238-245, 2006. [PubMed: 16364570] [Full Text: https://doi.org/10.1016/j.gene.2005.07.045]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Pippucci, T., Savoia, A., Perrotta, S., Pujol-Moix, N., Noris, P., Castegnaro, G., Pecci, A., Gnan, C., Punzo, F., Marconi, C., Gherardi, S., Loffredo, G., and 11 others. Mutations in the 5-prime UTR of ANKRD26, the ankirin (sic) repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am. J. Hum. Genet. 88: 115-120, 2011. [PubMed: 21211618] [Full Text: https://doi.org/10.1016/j.ajhg.2010.12.006]
Punzo, F., Mientjes, E. J., Rohe, C. F., Scianguetta, S., Amendola, G., Oostra, B. A., Bertoli-Avella, A. M., Perrotta, S. A mutation in the acyl-coenzyme A binding domain-containing protein 5 gene (ACBD5) identified in autosomal dominant thrombocytopenia. J. Thromb. Haemost. 8: 2085-2087, 2010. [PubMed: 20626622] [Full Text: https://doi.org/10.1111/j.1538-7836.2010.03979.x]
Savoia, A., Del Vecchio, M., Totaro, A., Perrotta, S., Amendola, G., Moretti, A., Zelante, L., Iolascon, A. An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p. Am. J. Hum. Genet. 65: 1401-1405, 1999. [PubMed: 10521306] [Full Text: https://doi.org/10.1086/302637]