Alternative titles; symbols
HGNC Approved Gene Symbol: ANKRD11
SNOMEDCT: 711156009;
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38) : 16:89,267,630-89,490,561 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | KBG syndrome | 148050 | Autosomal dominant | 3 |
ANKRD11 is a member of a family of ankyrin repeat-containing cofactors that interacts with p160 nuclear receptor coactivators (see NCOA1; 602691) and inhibits ligand-dependent transcriptional activation (Zhang et al., 2004).
Using yeast 2-hybrid analysis with the conserved N-terminal basic helix-loop-helix (bHLH) domain of p160 nuclear receptor coactivator RAC3 (NCOA3; 601937) as bait, Zhang et al. (2004) cloned ANKRD11, which they called ANCO1. The deduced 2,663-amino acid protein had a calculated molecular mass of 298 kD and contained five 33-amino acid ankyrin repeats, a highly charged central region, and many putative nuclear localization signals. Zhang et al. (2004) found that ANCO1 is identical to the previously isolated nasopharyngeal carcinoma susceptibility protein LZ16. Northern blot analysis detected a 10-kb transcript in many human tissues and cancer cell lines, with highest expression in skeletal muscle and chronic myeloid leukemia K562 cells. Smaller transcripts of 3.5 and 7.5 kb were detected. Immunofluorescence studies localized ANCO1 to discrete nuclear foci that colocalized with histone deacetylases HDAC3 (605166), HDAC4 (605314), and HDAC5 (605315) specifically.
Using nonquantitative RT-PCR, Sirmaci et al. (2011) confirmed expression of ANKRD11 in the human adult brain. Examination of transfected mouse neonatal cerebral cortical primary cultures using fluorescence microscopy revealed that ANKRD11 localized mainly to the nuclei of neurons and glial cells and only a relatively small amount was localized in the cytoplasm. Depolarization of the cells significantly induced nuclear accumulation of ANKRD11 in discrete inclusions.
By genomic sequence analysis, Zhang et al. (2004) mapped the ANKRD11 gene to chromosome 16q24.3.
Using yeast 2-hybrid and GST pull-down studies, Zhang et al. (2004) demonstrated that the C-terminal amino acids of ANCO1 (2597-2663) bound p160 nuclear coactivators RAC3, TIF2 (NCOA2; 601993), and SRC1 (NCOA1; 602691). By GST pull-down assay and coimmunoprecipitation studies, the authors showed that ANCO1 bound histone deacetylases HDAC3, HDAC4, and HDAC5 via an HDAC binding domain distinct from the ANCO1 p160 coactivator binding domain. Overexpression of ANCO1 inhibited transcriptional activation by nuclear receptors, including the mineralocorticoid (NR3C2; 600983), androgen (AR; 313700), progesterone (PGR; 607311), and glucocorticoid (GCCR; 138040) receptors. The results of competition studies with ANCO1 and p160 coactivator TIF2 suggested to Zhang et al. (2004) that ANCO1 inhibits ligand-dependent transactivation by recruiting HDACs to the coactivator/nuclear receptor complex.
In a Turkish family with macrodontia, mental retardation, characteristic facies, short stature, and skeletal anomalies (KBG syndrome, KBGS; 148050), originally reported by Tekin et al. (2004), Sirmaci et al. (2011) performed whole-exome capture followed by next-generation sequencing and identified a heterozygous splice site variant in the ANKRD11 gene (611192.0001) that segregated with disease and was not found in ethnically matched controls. Analysis of ANKRD11 in 9 additional KBGS probands revealed heterozygosity for truncating mutations in 4 of them (see, e.g., 611192.0002 and 611192.0003). All 5 mutations involved the highly conserved C-terminal repression domain of ANKRD11.
Ansari et al. (2014) identified 2 different de novo heterozygous truncating mutations in the ANKRD11 gene (see, e.g., 611192.0004) in 2 unrelated patients with KBG syndrome. A third unrelated patient had an intragenic deletion in the ANKRD11 gene. The patients were ascertained from a larger cohort of patients with features consistent with Cornelia de Lange syndrome (see, e.g., CDLS1, 122470), thus showing phenotypic overlap between the 2 disorders. All had normal head circumference; detailed clinical features were not provided.
Gnazzo et al. (2020) reported 31 patients (18 females and 13 males) with a heterozygous pathogenic variant in the ANKRD11 gene (28 patients) or a 16q24 deletion encompassing the ANKRD11 gene (3 patients) seen at a single hospital in Italy. All mutations affected the C-terminal region at exon 9 of ANKRD11, including 17 frameshift and 11 nonsense mutations. Testing was done on both parents in 18 patients; 16 ANKRD11 variants were found to be de novo and 2 were inherited from affected mothers.
By exome sequencing in a boy with features of KBG syndrome, Geckinli et al. (2022) identified a de novo heterozygous missense mutation in the AKRD11 gene (R1475S; 611192.0005). The mutation was not present in the proband's unaffected, first-cousin parents or in his sister, who had seizures but no other findings of KBG syndrome. The variant was not present in public variant databases, including ExAC, gnomAD, and 1000 Genomes Project. The authors stated that the variant was classified as a variant of unknown significance by ACMG criteria.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ANKRD11 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a father and 2 sons from a Turkish family with KBG syndrome (KBGS; 148050), originally reported by Tekin et al. (2004), Sirmaci et al. (2011) identified heterozygosity for a G-C transversion at the splice acceptor site (7570-1G-C) in intron 10 of the ANKRD11 gene, resulting in the deletion of 2 residues located in the highly conserved C-terminal repression domain (Glu2524_Lys2525del). The mutation was not found in the unaffected mother or in 339 Turkish controls. The 46-year-old father, who was the oldest affected individual studied by Sirmaci et al. (2011), had developed moderate kyphosis and osteopenia with age.
In a 16-year-old Turkish boy with KBG syndrome (KBGS; 148050), Sirmaci et al. (2011) identified heterozygosity for a de novo 1-bp deletion (2305delT) in exon 9 of the ANKRD11 gene, causing a frameshift predicted to result in a premature termination codon (Ser769GlnfsTer8). The mutation was not found in his unaffected parents or in 255 Turkish controls. Real-time PCR analysis of peripheral blood RNA from the patient demonstrated reduction of ANKRD11 expression compared to his father.
In a 21-year-old Italian man with KBG syndrome (KBGS; 148050), originally reported by Brancati et al. (2004), Sirmaci et al. (2011) identified heterozygosity for a de novo 2-bp deletion (5953_5954delCA) in exon 9 of the ANKRD11 gene, causing a frameshift predicted to result in a premature termination codon (Gln1985GlufsTer46). The mutation was not found in his unaffected parents or in 40 Italian controls.
In a girl with KBG syndrome (KBGS; 148050), Ansari et al. (2014) identified a de novo heterozygous 2-bp deletion (c.6210_6211del) in exon 7 of the ANKRD11 gene, resulting in a frameshift and premature termination (Lys2070AsnfsTer31). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was ascertained from a larger cohort of patients with features consistent with Cornelia de Lange syndrome (see, e.g., CDLS1, 122470), thus showing phenotypic overlap between the 2 disorders.
This variant is classified as a variant of unknown significance because its contribution to KBG syndrome (KBGS; 148050) has not been confirmed.
In a boy with KBG syndrome, Geckinli et al. (2022) identified a de novo heterozygous c.4425G-T transversion (c.4425G-T, NM_001256182) in exon 10 of the ANKRD11 gene, resulting in an arg1475-to-ser (R1475S) substitution. The variant was not found in public population databases, including ExAC, gnomAD, and 1000 Genomes Project. The variant was not present in the proband's unaffected, first-cousin parents or in his sister, who also had seizures but no other features of KBG syndrome. The authors stated that the variant was classified as a variant of unknown significance by ACMG criteria.
Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J. Med. Genet. 51: 659-668, 2014. [PubMed: 25125236] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102573]
Brancati, F., D'Avanzo, M. G., Digilio, M. C., Sarkozy, A., Biondi, M., De Brasi, D., Mingarelli, R., Dallapiccola, B. KBG syndrome in a cohort of Italian patients. Am. J. Med. Genet. 131A: 144-149, 2004. [PubMed: 15523620] [Full Text: https://doi.org/10.1002/ajmg.a.30292]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Geckinli, B. B., Alavanda, C., Arslan Ates, E., Yildirim, O., Arman, A. Enostosis in a patient with KBG syndrome caused by a novel missense ANKRD11 variant. Clin. Dysmorph. 31: 153-156, 2022. [PubMed: 35394473] [Full Text: https://doi.org/10.1097/MCD.0000000000000421]
Gnazzo, M., Lepri, F. R., Dentici, M. L., Capolino, R., Pisaneschi, E., Agolini, E., Rinelli, M., Alesi, V., Versacci, P., Genovese, S., Cesario, C., Sinibaldi, L., Baban, A., Bartuli, A., Marino, B., Cappa, M., Dallapiccola, B., Novelli, A., Digilio, M. C. KBG syndrome: Common and uncommon clinical features based on 31 new patients. Am. J. Med. Genet. 182A: 1073-1083, 2020. [PubMed: 32124548] [Full Text: https://doi.org/10.1002/ajmg.a.61524]
Sirmaci, A., Spiliopoulos, M., Brancati, F., Powell, E., Duman, D., Abrams, A., Bademci, G., Agolini, E., Guo, S., Konuk, B., Kavaz, A., Blanton, S., Digilio, M. C., Dallapiccola, B., Young, J., Zuchner, S., Tekin, M. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am. J. Hum. Genet. 89: 289-294, 2011. [PubMed: 21782149] [Full Text: https://doi.org/10.1016/j.ajhg.2011.06.007]
Tekin, M., Kavaz, A., Berberoglu, M., Fitoz, S., Ekim, M., Ocal, G., Akar, N. The KBG syndrome: confirmation of autosomal dominant inheritance and further delineation of the phenotype. Am. J. Med. Genet. 130A: 284-287, 2004. [PubMed: 15378538] [Full Text: https://doi.org/10.1002/ajmg.a.30291]
Zhang, A., Yeung, P. L., Li, C.-W., Tsai, S.-C., Dinh, G. K., Wu, X., Li, H., Chen, J. D. Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. J. Biol. Chem. 279: 33799-33805, 2004. [PubMed: 15184363] [Full Text: https://doi.org/10.1074/jbc.M403997200]