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Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.
- Source :
-
Nature genetics [Nat Genet] 2002 Feb; Vol. 30 (2), pp. 181-4. Date of Electronic Publication: 2002 Jan 22. - Publication Year :
- 2002
-
Abstract
- Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
- Subjects :
- Adenine Nucleotides metabolism
Base Sequence
Case-Control Studies
DNA Mutational Analysis
DNA, Neoplasm genetics
Female
Genetic Linkage
Heterozygote
Homozygote
Humans
Loss of Heterozygosity
Lymphocytes enzymology
Male
Oligoribonucleotides metabolism
Pedigree
Endoribonucleases genetics
Germ-Line Mutation
Oncogenes
Prostatic Neoplasms enzymology
Prostatic Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1061-4036
- Volume :
- 30
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 11799394
- Full Text :
- https://doi.org/10.1038/ng823