Alternative titles; symbols
HGNC Approved Gene Symbol: NTHL1
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:2,039,820-2,047,834 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Familial adenomatous polyposis 3 | 616415 | Autosomal recessive | 3 |
DNA N-glycosylases, or apurinic/apyrimidinic lyases, of the endonuclease III family, such as NTHL1, initiate DNA base excision repair of oxidized ring saturated pyrimidine residues (Ocampo et al., 2002).
The European Chromosome 16 Tuberous Sclerosis Consortium (1993) identified a gene, termed OCTS3, that lies next to TSC2 (191092) in a head-to-head orientation on chromosome 16. Aspinwall et al. (1997) cloned a corresponding cDNA and showed that OCTS3 encodes a human homolog of E. coli endonuclease III. They renamed the human gene NTH1, in reference to the E. coli 'nth' gene. The human NTH1 gene encodes a 312-amino acid polypeptide with a predicted mass of 34.3 kD. When expressed and purified, the protein had the same enzymatic activities as the E. coli enzyme: DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues, and apurinic/apyrimidinic lyase activity.
Based on peptide sequences of purified bovine endonuclease III and sequences in the expressed sequence tag database (dbEST), Hilbert et al. (1997) also cloned a human NTH1 cDNA.
Using Northern blot analysis, Imai et al. (1998) found ubiquitous but variable expression of a 1.0-kb NTHL1 transcript.
Imai et al. (1998) cloned the NTHL1 gene and showed that it contains 6 exons spanning approximately 8 kb of genomic DNA. Promoter analysis indicated a lack of TATA and CAAT boxes but the presence of a CpG island with binding sites for several transcription factors.
Hilbert et al. (1997) used fluorescence in situ hybridization to localize the NTHL1 gene to chromosome 16p13.3-p13.2.
In 7 affected individuals from 3 unrelated families with familial adenomatous polyposis-3 (FAP3; 616415), Weren et al. (2015) identified a homozygous truncating mutation in the NTHL1 gene (Q90X; 602656.0001), which encodes a base excision repair gene. The mutation was found by whole-exome sequencing of 51 patients from 48 families with predisposition to colonic adenomatous polyposis, and was confirmed by Sanger sequencing to segregate with the disorder in the 3 families. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA decay, consistent with a loss of function.
In a German woman with FAP3 and multiple additional extracolonic neoplasms, Rivera et al. (2015) identified compound heterozygous mutations in the NTHL1 gene (602656.0001 and 602656.0002). Six different tumors from the proband were found to carry somatic mutations in driver genes, such as FGFR3 (134934). Rivera et al. (2015) noted that 6 of the 7 patients reported by Weren et al. (2015) had a diagnosis of multiple primary tumors, suggesting that NTHL1 mutations can cause a wide variety of cancers in addition to colorectal cancer. Rivera et al. (2015) suggested the designation 'NTHL1 syndrome' for this cancer predisposition syndrome.
Ocampo et al. (2002) found that the phenotype of Nth1 -/- mice was indistinguishable from that of wildtype mice. They found that loss of Nth1 activity was compensated for by enzymatic activity that recognized oxidized thymine in DNA, particularly when paired with guanine.
In 7 affected individuals from 3 unrelated families with familial adenomatous polyposis-3 (FAP3; 616415), Weren et al. (2015) identified a homozygous c.268C-T transition (c.268C-T, NM_002528) in the NTHL1 gene, resulting in a gln90-to-ter (Q90X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against an in-house exome database of 2,037 control individuals. A heterozygous Q90X mutation was found at a frequency of 0.0036 among 2,329 controls and of 0.0015 in the Exome Aggregation Consortium (ExAC) database; the highest prevalence of the mutation was found in individuals of European descent. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Genetic analysis of 3 carcinomas and 5 adenomas from different affected individuals showed a nonhypermutated profile enriched for C-to-T transitions, and the carcinomas carried somatic mutations in several genes, including APC (611731), TP53 (191170), KRAS (190070), and PIK3CA (171834).
In a German woman with familial adenomatous polyposis-3 (FAP3; 616415) and multiple additional extracolonic neoplasms, Rivera et al. (2015) identified compound heterozygous mutations in the NTHL1 gene: a c.709+1G-A transition in intron 4 (c.709+1G-A, NM_002528), resulting in a splice site defect that was detectable in patient cells, and Q90X (602656.0001). The patient developed colonic adenocarcinoma at age 41, and was later found to have bladder carcinoma, intradermal nevi, meningioma, multiple seborrheic keratoses, basal cell carcinoma, multiple colorectal adenomas, squamous cell carcinoma, and invasive ductal carcinoma. Six different tumors from the proband were found to carry somatic mutations in driver genes, such as FGFR3 (134934). She also had a family history of cancer.
Aspinwall, R., Rothwell, D. G., Roldan-Arjona, T., Anselmino, C., Ward, C. J., Cheadle, J. P., Sampson, J. R., Lindahl, T., Harris, P. C., Hickson, I. D. Cloning and characterization of a functional human homolog of Escherichia coli endonuclease III. Proc. Nat. Acad. Sci. 94: 109-114, 1997. [PubMed: 8990169] [Full Text: https://doi.org/10.1073/pnas.94.1.109]
Hilbert, T. P., Chaung, W., Boorstein, R. J., Cunningham, R. P., Teebor, G. W. Cloning and expression of the cDNA encoding the human homologue of the DNA repair enzyme, Escherichia coli endonuclease III. J. Biol. Chem. 272: 6733-6740, 1997. [PubMed: 9045706] [Full Text: https://doi.org/10.1074/jbc.272.10.6733]
Imai, K., Sarker, A. H., Akiyama, K., Ikeda, S., Yao, M., Tsutsui, K., Shohmori, T., Seki, S. Genomic structure and sequence of a human homologue (NTHL1/NTH1) of Escherichia coli endonuclease III with those of the adjacent parts of TSC2 and SLC9A3R2 genes. Gene 222: 287-295, 1998. [PubMed: 9831664] [Full Text: https://doi.org/10.1016/s0378-1119(98)00485-5]
Ocampo, M. T. A., Chaung, W., Marenstein, D. R., Chan, M. K., Altamirano, A., Basu, A. K., Boorstein, R. J., Cunningham, R. P., Teebor, G. W. Targeted deletion of mNth1 reveals a novel DNA repair enzyme activity. Molec. Cell. Biol. 22: 6111-6121, 2002. [PubMed: 12167705] [Full Text: https://doi.org/10.1128/MCB.22.17.6111-6121.2002]
Rivera, B., Castellsague, E., Bah, I., and others. Biallelic NTHL1 mutations in a woman with multiple primary tumors. (Letter) New Eng. J. Med. 373: 1985-1986, 2015. Note: Full author list online. Erratum: New Eng. J. Med. 373: e33, 2015. [PubMed: 26559593] [Full Text: https://doi.org/10.1056/NEJMc1506878]
The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75: 1305-1315, 1993. [PubMed: 8269512] [Full Text: https://doi.org/10.1016/0092-8674(93)90618-z]
Weren, R. D. A., Ligtenberg, M. J. L., Kets, C. M., de Voer, R. M., Verwiel, E. T. P., Spruijt, L., van Zelst-Stams, W. A. G., Jongmans, M. C., Gilissen, C., Hehir-Kwa, J. Y., Hoischen, A., Shendure, J., and 9 others. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nature Genet. 47: 668-671, 2015. [PubMed: 25938944] [Full Text: https://doi.org/10.1038/ng.3287]