Defective NTHL1 substrate binding

Stable Identifier
Homo sapiens
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Several different mutations that result in truncation of NTHL1 protein have been described and associated with cancer. NTHL1 Q90TER (NTHL1 Gln90*) truncation mutant results from a nonsense mutation that replaces codon for glutamine 90 with a STOP codon. NTHL1 Q90TER has not been studied at the protein level, but is predicted to lack the DNA binding domain and the glycosylase domain, thus resulting in a complete loss of the base excision repair (BER) related DNA glycosylase function. Homozygous or compound heterozygous germline NTHL1 Q90TER mutation result in a cancer syndrome (NTHL1 associated tumor syndrome) that involves adenomatous polyposis, colorectal cancer breast cancer and multiple other types of cancer and benign tumors (Weren et al. 2015, Rivera et al. 2015, Grolleman et al. 2019). Apart from NTHL1 Q90TER, at least seven other truncating variants have been identified in patients with NTHL1 associated tumor syndrome, such as NTHL1 A79fs (NTHL1 Ala79fs), NTHL1 Y130TER (NTHL1 Tyr130*), NTHL1 W182TER (NTHL1 Trp182*), NTHL1 c.709+1G>A, NTHL1 I245fs (NTHL1 Ile245fs), NTHL1 W269TER (NTHL1 Trp269*), NTHL1 Q287TER (NTHL1 Gln287*) (Rivera et al. 2015, Broderick et al. 2017, Grolleman et al. 2019).
Literature References
PubMed ID Title Journal Year
30753826 Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Sweet, K, Hüneburg, R, Høberg-Vetti, H, Morreau, H, Campbell, IG, Cockburn, D, Kuiper, RA, Ten Broeke, SW, Vink-Börger, ME, Palles, C, Lubinski, J, Sjursen, W, Nielsen, M, de Miranda, NFCC, Schindler, D, Lindsay, H, Lang, A, Hes, FJ, Staninova, M, Elsayed, FA, Clendenning, M, Adlard, J, Li, N, Kamping, EJ, Jongmans, MC, de Voer, RM, Hoogerbrugge, N, Geurts van Kessel, A, Kuiper, RP, van Wezel, T, Ligtenberg, MJL, Aretz, S, Vos, JR, Spasic-Boskovic, O, James, PA, Capellá, G, Valle, L, Grolleman, JE, Ruiz-Ponte, C, Foulkes, WD, Kenwrick, S, Jansen, EAM, Rivera, B, Spier, I, Sijmons, RH, Schackert, HK, Popp, I, Buchanan, DD, Dimovski, AJ, Weren, RDA, Neveling, K, Tomlinson, IP, Dymerska, D

Cancer Cell 2019
27713038 Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review

Broderick, P, Kinnersley, B, Tomlinson, I, Dobbins, SE, Chubb, D, Houlston, RS, Dunlop, MG

Gastroenterology 2017
25938944 A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Weren, RD, Kuiper, RP, Ligtenberg, MJ, Geurts van Kessel, A, Hoogerbrugge, N, Verwiel, ET, de Voer, RM, Jongmans, MC, Kamping, EJ, Hoischen, A, van Krieken, JH, Nagtegaal, ID, van Zelst-Stams, WA, Nagengast, FM, Spruijt, L, Tops, BB, Hehir-Kwa, JY, Boyle, EA, Gilissen, C, Shendure, J, Kets, CM

Nat. Genet. 2015
26559593 Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors

Castellsagué, E, Bah, I, van Kempen, LC, Rivera, B, Foulkes, WD

N. Engl. J. Med. 2015
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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