Alternative titles; symbols
HGNC Approved Gene Symbol: ACD
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38) : 16:67,657,512-67,660,260 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | ?Dyskeratosis congenita, autosomal dominant 6 | 616553 | Autosomal dominant; Autosomal recessive | 3 |
| ?Dyskeratosis congenita, autosomal recessive 7 | 616553 | Autosomal dominant; Autosomal recessive | 3 |
The ACD gene encodes one of the core proteins in the telomeric shelterin complex; it is necessary for recruitment of telomerase (see TERT, 187270) to telomeres (summary by Kocak et al., 2014, Guo et al., 2014).
By database analysis and RT-PCR of HeLa cell mRNA, Liu et al. (2004) cloned PTOP. The deduced 544-amino acid protein contains a pro-trp-ile (PWI) motif, followed by a central POT1 (606478) recruitment domain and a serine-rich region. Compared with bovine, mouse, and pufferfish Ptop, human PTOP has an additional 86 N-terminal amino acids. By database analysis, Liu et al. (2004) identified 2 PTOP splice variants with in-frame deletions that encode proteins with deletions in the PWI domain or following the serine-rich region. PTOP was expressed in all human tissues examined. Immunofluorescence microscopy detected PTOP in a punctate pattern that colocalized with telomere proteins.
The protein encoded by the ACD gene is sometimes referred to as TPP1. TPP1 is the HGNC approved gene symbol for tripeptidyl peptidase I (607998).
By SDS-PAGE of fractionated HeLa cell nuclear extracts and immunoprecipitation analysis, Liu et al. (2004) found that PTOP was associated with endogenous TIN2 (TINF2; 604319), POT1, and TRF2 (TERF2; 602027) in a high-molecular-mass complex. Deletion analysis indicated that the C-terminal half of PTOP interacted with TIN2, whereas the central domain of PTOP interacted with the C-terminal half of POT1. PTOP was essential for targeting POT1 to telomeres, and expression of the POT1 recruitment domain of PTOP functioned in a dominant-negative manner, blocking the interaction of POT1 with telomeres and permitting telomere extension.
Ye et al. (2004) found that PTOP, which they called PIP1, bound both POT1 and TIN2 and could tether POT1 to the TRF1 complex. Reduction of PTOP or POT1 levels with short hairpin RNAs led to telomere elongation, indicating that PTOP contributes to telomere length control through recruitment of POT1.
Through reconstitution and fractionation experiments, O'Connor et al. (2006) found that TPP1 and TIN2 were essential mediators of telomeric complex formation and that TPP1-TIN2 interaction regulated bridging of TRF1 (TERF1; 600951) and TRF2. Overexpression of TPP1 enhanced TIN2-TRF1 association, and conversely, knockdown of TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex. O'Connor et al. (2006) concluded that coordinated interaction among TPP1, TIN2, TRF1, and TRF2 is required for assembly of the telomere complex and ultimately for telomere maintenance.
Xin et al. (2007) demonstrated that TPP1 contains a predicted amino-terminal oligonucleotide/oligosaccharide-binding (OB) fold. TPP1-POT1 association enhanced POT1 affinity for telomeric single-stranded DNA. In addition, the TPP1 OB fold, as well as POT1-TPP1 binding, seemed critical for POT1-mediated telomere length control and telomere end protection in human cells. Disruption of POT1-TPP1 interaction by dominant-negative TPP1 expression or RNA interference resulted in telomere length alteration and DNA damage responses. Furthermore, Xin et al. (2007) offered evidence that TPP1 associates with telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex (a 6-protein complex thought to protect the telomeres of human chromosomes). Xin et al. (2007) concluded that their findings highlighted the critical role of TPP1 in telomere maintenance, and supported a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA.
Miyoshi et al. (2008) reported that Tpz1, the TPP1 homolog in fission yeast, forms a complex with Pot1 (606478). Tpz1 binds to Ccq1 and Poz1 (Pot1-associated in Schizosaccharomyces pombe), which protect telomeres redundantly and regulate telomerase in positive and negative manners, respectively. Thus, Miyoshi et al. (2008) concluded that the Pot1-Tpz1 complex accomplishes its functions by recruiting effector molecules Ccq1 and Poz1. Moreover, Poz1 bridges Pot1-Tpz1 and Taz1-Rap1, thereby connecting the single-stranded and double-stranded telomeric DNA regions. Miyoshi et al. (2008) suggested that such molecular architectures are similar to those of mammalian shelterin, indicating that overall DNA-protein architecture is conserved across evolution.
Nandakumar et al. (2012) identified separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The 7 separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these 2 activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a target for anticancer drug development.
Wang et al. (2007) demonstrated the crystal structure of a domain of human TPP1 to reveal an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme telomerase. In contrast, Wang et al. (2007) found that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. Wang et al. (2007) proposed that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.
Liu et al. (2004) stated that the ACD gene maps to chromosome 16q22.1.
Dyskeratosis Congenita 6, Autosomal Dominant
In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; 616533) manifest as progressive bone marrow failure, Guo et al. (2014) identified a heterozygous in-frame 3-bp deletion in the ACD gene (K140del; 609377.0001). Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. The findings indicated that a defect in TPP1 renders telomerase unable to maintain telomeres during development and hematopoiesis, leading to short telomeres and progressive bone marrow failure.
Dyskeratosis Congenita 7, Autosomal Recessive
In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see 616553), Kocak et al. (2014) identified compound heterozygous mutations in the ACD gene: K170del and P491T (609377.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father and sister, who had short telomeres, were heterozygous for the K170del mutation; the patient's mother, who was unaffected, was heterozygous for the missense mutation. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; 602322) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (604319) association. Kocak et al. (2014) concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation.
Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. Keegan et al. (2005) identified a splice donor mutation in the Acd gene in acd mice. Expression of a wildtype Acd transgene in acd mutants rescued the observed phenotype. Most mutants died within 1 to 2 days of life on the original genetic background. Analysis of mutant embryos revealed variable defects in caudal specification, limb patterning, and axial skeleton formation. In the tail bud, reduced expression of Wnt3a (606359) and DLL1 (606582) correlated with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 (600483) was expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos showed abnormal vertebral fusions in cervical, lumbar, and caudal regions.
Dyskeratosis Congenita, Autosomal Dominant 6
In 3 female members in 3 subsequent generations of a family with autosomal dominant dyskeratosis congenita-6 (DKCA6; 616553) manifest as progressive bone marrow failure, Guo et al. (2014) identified a heterozygous in-frame 3-bp deletion (c.499_501del, NM_001082486.1) in the ACD gene, resulting in the deletion of conserved residue lys170 (K170del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases. Lys170 localizes to the surface of the TPP1 protein known as the TEL patch, known to be vital for binding to telomerase. Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres.
Dyskeratosis Congenita, Autosomal Recessive 7
In a boy with autosomal recessive dyskeratosis congenita-7 (DKCB7; see 616553) manifest as Hoyeraal-Hreidarsson syndrome, Kocak et al. (2014) identified compound heterozygous mutations in the ACD gene: a 3-bp deletion (c.508_510delAAG, NM_001082486.1), resulting in K170del, which was inherited from his father who had premature graying of the hair, short telomeres, and mild dental abnormalities, and a c.1471C-A transversion, resulting in a pro491-to-thr (P491T; 609377.0002) substitution at a conserved residue in the C-terminal TIN2-interacting domain, which was inherited from the unaffected mother. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The K170del mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project (ESP) databases or in an in-house control database. The P401T variant was found in the dbSNP database and in the ESP database at a low frequency (0.0002), but was not present in the 1000 Genomes Project database or in the in-house control database. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; 602322) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (604319) association. Kocak et al. (2014) concluded that the detrimental effect of the P491T mutation was modest compared to the effect of the K170del mutation.
For discussion of the c.1471C-A transversion in the ACD gene, resulting in a pro491-to-thr (P491T) substitution, that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-7 (DKCB7; 616553) by Kocak et al. (2014), see 609377.0001.
Guo, Y., Kartawinata, M., Li, J., Pickett, H. A., Teo, J., Kilo, T., Barbaro, P. M., Keating, B., Chen, Y., Tian, L., Al-Odaib, A., Reddel, R. R., Christodoulou, J., Xu, X., Hakonarson, H., Bryan, T. M. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 124: 2767-2774, 2014. [PubMed: 25205116] [Full Text: https://doi.org/10.1182/blood-2014-08-596445]
Keegan, C. E., Hutz, J. E., Else, T., Adamska, M., Shah, S. P., Kent, A. E., Howes, J. M., Beamer, W. G., Hammer, G. D. Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Hum. Molec. Genet. 14: 113-123, 2005. [PubMed: 15537664] [Full Text: https://doi.org/10.1093/hmg/ddi011]
Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J., Savage, S. A. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev. 28: 2090-2102, 2014. [PubMed: 25233904] [Full Text: https://doi.org/10.1101/gad.248567.114]
Liu, D., Safari, A., O'Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., Songyang, Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nature Cell Biol. 6: 673-680, 2004. [PubMed: 15181449] [Full Text: https://doi.org/10.1038/ncb1142]
Miyoshi, T., Kanoh, J., Saito, M., Ishikawa, F. Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science 320: 1341-1344, 2008. [PubMed: 18535244] [Full Text: https://doi.org/10.1126/science.1154819]
Nandakumar, J., Bell, C. F., Weidenfeld, I., Zaug, A. J., Leinwand, L. A., Cech, T. R. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492: 285-289, 2012. [PubMed: 23103865] [Full Text: https://doi.org/10.1038/nature11648]
O'Connor, M. S., Safari, A., Xin, H., Liu, D., Songyang, Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc. Nat. Acad. Sci. 103: 11874-11879, 2006. [PubMed: 16880378] [Full Text: https://doi.org/10.1073/pnas.0605303103]
Wang, F., Podell, E. R., Zaug, A. J., Yang, Y., Baciu, P., Cech, T. R., Lei, M. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445: 506-510, 2007. [PubMed: 17237768] [Full Text: https://doi.org/10.1038/nature05454]
Xin, H., Liu, D., Wan, M., Safari, A., Kim, H., Sun, W., O'Connor, M. S., Songyang, Z. TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445: 559-562, 2007. [PubMed: 17237767] [Full Text: https://doi.org/10.1038/nature05469]
Ye, J. Z.-S., Hockemeyer, D., Krutchinsky, A. N., Loayza, D., Hooper, S. M., Chait, B. T., de Lange, T. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18: 1649-1654, 2004. [PubMed: 15231715] [Full Text: https://doi.org/10.1101/gad.1215404]