Alternative titles; symbols
HGNC Approved Gene Symbol: ELAC2
SNOMEDCT: 775908005;
Cytogenetic location: 17p12 Genomic coordinates (GRCh38): 17:12,991,612-13,018,027 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p12 | {Prostate cancer, hereditary, 2, susceptibility to} | 614731 | 3 | |
| Combined oxidative phosphorylation deficiency 17 | 615440 | Autosomal recessive | 3 |
ELAC2 encodes the long form of RNase Z (EC 3.1.26.11), an endonuclease responsible for the removal of the 3-prime extensions from tRNA precursors, an essential step in tRNA biogenesis. Alternative translation initiation is responsible for the dual targeting of RNase Z(L) to the nucleus and to the mitochondria (Rossmanith, 2011).
By positional cloning in a region of chromosome 17p associated with prostate cancer in high-risk Utah families, Tavtigian et al. (2000, 2001) identified the HPC2/ELAC2 gene. They assembled the human and mouse ELAC2 cDNA sequences from a combination of ESTs, hybrid selected clones, and 5-prime RACE products. The deduced human protein contains 826 amino acids with a predicted metal-dependent hydrolase domain that is conserved among eukaryotes, archebacteria, and eubacteria. Its sequence shares similarity with 2 protein families, namely the PSO2/SNM1 DNA interstrand cross-link repair proteins (see DCLRE1A; 609682) and the 73-kD subunit of mRNA 3-prime end cleavage and polyadenylation specificity factor (CPSF73; 606029). RNA-blot analysis revealed a single ELAC2 transcript of approximately 3 kb. The transcript was detected in all tissues tested, with highest expression in testis.
Using PCR, Rossmanith (2011) cloned RNase ZL from HeLa cells. The deduced full-length 826-amino acid protein has an N-terminal mitochondrial localization signal with a predicted overlapping nuclear targeting signal beginning at residue 28. Rossmanith (2011) noted that the start codon for full-length RNase ZL is in a suboptimal context for translation. A putative downstream start codon, in a more favorable context, would encode an N-terminally truncated protein lacking the first 15 residues of the mitochondrial localization signal. C-terminally fluorescence-tagged RNase ZL localized to both mitochondria and nucleus, but not cytosol, in transfected HEK293 cells and 143B osteosarcoma cells. In contrast, RNase ZS (ELAC1; 608079) localized predominantly to the cytosol.
Brzezniak et al. (2011) found that epitope-tagged ELAC2 localized to both nucleus and mitochondria in transfected human cell lines. Endogenous ELAC2 also localized to nucleus and mitochondria in human cell lines.
Tavtigian et al. (2001) identified the ELAC2 gene on chromosome 17p in an approximately 1.5-Mb interval flanked by 17-MYR0024 and D17S936. Xu et al. (2001) gave 17p11 as the position of the HPC2/ELAC2 gene.
Using mutant RNase ZL constructs with the first translational initiation codon in a more favorable initiation context than wildtype, as well as a construct encoding RNase ZL lacking the first 15 N-terminal amino acids, Rossmanith (2011) showed that alternative usage of start codons in RNase ZL resulted in either mitochondrial or nuclear localization. Rossmanith (2011) hypothesized that RNase ZL has a role in 3-prime end maturation of both nuclear and mitochondrial encoded tRNAs.
Using RT-PCR and Northern blot analyses, Brzezniak et al. (2011) found that silencing the human ELAC2 gene resulted in accumulation of several mitochondrial tRNA precursors with unprocessed 3-prime ends. Silencing of MRPP1 (TRMT10C; 615423), which encodes a subunit of mitochondrial RNase P, a 5-prime tRNA precursor-processing enzyme, resulted in accumulation of tRNA precursors with unprocessed 5-prime and 3-prime ends. Brzezniak et al. (2011) concluded that tRNase Z preferentially acts after RNase P and can only process RNA already cleaved at the tRNA 5-prime end.
Hereditary Prostate Cancer 2
In Utah families at high risk for early-onset prostate cancer (HPC2; 614731), Tavtigian et al. (2000, 2001) identified 2 common missense variants in the ELAC2 gene that were associated with a diagnosis of prostate cancer: a ser-to-leu change at amino acid 217 (S217L; 605367.0001), and an ala-to-thr change at amino acid 541 (A541T; 605367.0002).
In a sample of cases unselected for family history, Rebbeck et al. (2000) studied the relationship of the 2 missense variants identified by Tavtigian et al. (2000) with the probability of having prostate cancer. They studied 359 subjects with prostate cancer and 266 male control subjects matched for age and race. Among control subjects, the thr541 frequency was 2.9%, and the leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was observed only in men who also carried leu217. The probability of having prostate cancer was increased in men who carried the leu217/thr541 variant (odds ratio = 2.37; 95% confidence interval 1.06-5.29). This risk also did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of prostate cancer in the general population studied.
To investigate the relationship between HPC2 and prostate cancer risk, Xu et al. (2001) performed the following analyses: (1) a linkage study of 6 markers in and around the HPC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer; (2) a mutation screening analysis of all coding exons of the gene in 93 probands with hereditary prostate cancer; and (3) a family-based and population-based association study of common HPC2 missense variants in 159 probands with hereditary prostate cancer, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample or in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the 2 previously reported missense changes, S217L and A541T, were identified by mutation analysis of all HPC2 exons in 93 probands with HPC. Xu et al. (2001) concluded that, considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies, the results could not rule out the possibility of a highly penetrant prostate cancer gene at this locus that segregates in only a small number of pedigrees. Nor could they rule out a prostate cancer modifier gene that confers a lower than reported risk.
Vesprini et al. (2001) investigated whether the S217L and A541T variants could be informative in the prediction of the presence of prostate cancer in men undergoing biopsy for the evaluation of an elevated serum prostate-specific antigen (PSA; 176820) level (4.0 ng/ml or more). They genotyped a control population of unselected women from the same population. The prevalence of the HPC2 A541T allele was similar in men with prostate cancer (6.3%), men with other prostate conditions (6.8%), and healthy women (6.3%). The authors concluded that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.
Tavtigian et al. (2001) identified 2 additional mutations in the ELAC2 gene in 2 Utah families at high-risk for prostate cancer: an insertion/frameshift mutation (1641insG; 605367.0003) and a missense mutation (R781H; 605367.0004).
Rokman et al. (2001) screened for mutations of the ELAC2 gene in 66 Finnish hereditary prostate cancer families. Several sequence variants, including a novel exonic variant (E622V; 605367.0005), were found, but none of the mutations was truncating. They then analyzed the frequency of 3 missense mutations in 1,365 individuals, including 107 hereditary and 467 unselected prostate cancer patients, 223 patients with benign prostatic hyperplasia (600082), and 568 healthy male controls. S217L (605367.0001) and A541T (605367.0002) carried no significantly elevated risk for prostate cancer, although the latter variant was associated with benign prostatic hyperplasia. The E622V variant had a 1.0% population prevalence, but a significantly higher frequency in prostate cancer cases (3.0%, odds ratio, 2.94; 95% CI, 1.05-8.23). Rokman et al. (2001) concluded that ELAC2 truncating mutations are rare in HPC, but that rare variants require additional study as risk factors for prostate cancer in the general population.
In a study at the Mayo Clinic, Wang et al. (2001) likewise concluded that alterations in the ELAC2 gene play a limited role in genetic susceptibility to HPC. The frequency of the leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the thr541 variant. Furthermore, they found no association of the joint effects of leu217 and thr541.
In a study of Afro-Caribbean males from Tobago, Shea et al. (2002) noted the absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls. They concluded that ELAC2 does not significantly contribute to the elevated prevalence of prostate cancer in this population.
Combined Oxidative Phosphorylation Deficiency 17
In 5 patients from 3 unrelated families with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440) manifest as severe infantile-onset hypertrophic cardiomyopathy, Haack et al. (2013) identified compound heterozygous or homozygous mutations in the ELAC2 gene (605367.0006-605367.0009). The initial mutations were found be exome sequencing. In addition to cardiomyopathy, which resulted in death in childhood in 3 patients, affected individuals had hypotonia, lactic acidosis, poor growth, and delayed psychomotor development. Biochemical studies in patient skeletal muscle showed decreased mitochondrial complex I activity; some cells also showed decreases in complex IV. Patient tissue samples showed accumulation of unprocessed mt-tRNA intermediates that could be rescued by expression of wildtype ELAC2. The findings were consistent with impaired 3-prime end processing of mt-tRNAs. Although levels of mature mt-tRNA, mt-mRNA, and mt-rRNA were normal, patient cells showed increased levels of unprocessed mt-mRNA and mt-rRNA precursors and evidence of decreased translation of mitochondrial proteins. Haack et al. (2013) concluded that impaired RNase Z activity of ELAC2 causes a fatal failure in cellular energy metabolism by interfering with normal mitochondrial translation.
Rebbeck et al. (2000) demonstrated an increased risk of prostate cancer (HPC2; 614731) in individuals carrying 1 or both of 2 common missense variants identified by Tavtigian et al. (2000): the leu217 allele of the ser217-to-leu (S217L) polymorphism and the thr541 allele of the ala541-to-thr (A541T) polymorphism (605367.0002). The A541T missense variant lies adjacent to a conserved histidine motif, suggesting that the presence of a thr541 allele may have deleterious effects on the function of the protein encoded by this gene.
Fujiwara et al. (2002) genotyped the S217L and A541T variants in a Japanese cohort consisting of 350 prostate cancer patients, 242 male population controls, and 114 male low-risk controls. Both the leu217 and thr541 alleles were carried at higher frequency in patients than in controls, and the odds ratios associated with these variants were higher in Japanese than in Caucasians. The leu217 and thr541 polymorphisms are less common in Japanese than in Caucasians, but both confer significantly increased risk of prostate cancer in Japanese.
For discussion of the ala541-to-thr (A541T) mutation in the ELAC2 gene that was found in compound heterozygous state in individuals with an increased risk of prostate cancer (HPC2; 614731) by Rebbeck et al. (2000), see 605367.0001.
Camp and Tavtigian (2002) performed a metaanalysis indicating that carriage of the thr541 allele, either alone or in combination with carriage of the leu217 allele (605367.0001), is significantly associated with prostate cancer. The summary analysis of leu217 data did not support the original finding of Tavtigian et al. (2001) that homozygotes for leu217 are at increased risk of prostate cancer. A very modest dominant effect may indicate that the best model for leu217 is codominant. The analyses further suggested that the original maximal odds ratio (OR) risk estimates of 3.1 and 2.37 for carriage of thr541 for ELAC2 variants on prostate cancer risk were inflated. An OR of 1.3, which translates to a population-attributable risk of 2%, was considered more realistic. The summary analyses provided convincing evidence for the role of ELAC2 in prostate cancer, suggested moderate familial risk, and estimated that risk genotypes in ELAC2 may cause 2% of prostate cancer in the general population.
Tavtigian et al. (2001) demonstrated an insertion/frameshift, 1641insG, in the ELAC2 gene in a Utah family with 8 prostate cancer cases (HPC2; 614731) in 3 generations. Insertion of a nucleotide between residues 1641 and 1642 shifted the reading frame after leu547, leading to termination after the miscoding of 67 residues. The mutation segregated with disease in this family.
In a patient with prostate cancer (HPC2; 614731) diagnosed at the age of 50, Tavtigian et al. (2001) found an arg781-to-his (R781H) mutation in the ELAC2 gene. The mutation was traced back through 4 generations to a man who had affected descendants from 5 wives. Prostate cancer cases carrying the missense change had been found among the descendants from 3 of these 5 marriages. In addition, a female carrier of the mutation was diagnosed with ovarian cancer at age 43. Within the generations with phenotype information, there were only 2 unaffected males over age 45 who carried the mutation.
In the proband of a Finnish family segregating hereditary prostate cancer (HPC2; 614731), Rokman et al. (2001) identified homozygosity for an A-to-T transversion at nucleotide 1865 in exon 20 of the ELAC2 gene, resulting in a glu622-to-val (E622V) substitution.
In 2 brothers with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440), Haack et al. (2013) identified compound heterozygous mutations in the ELAC2 gene: a c.631C-T transition in exon 7 resulting in an arg211-to-ter (R211X) substitution, and a c.1559C-T transition in exon 17 resulting in a thr520-to-ile (T520I; 605367.0007) substitution at a conserved residue in a metallo-beta-lactamase superfamily domain. The mutations in 1 sib were found by exome sequencing and were present at less than 0.2% frequency in 1,846 control exomes and public databases. Each unaffected parent was heterozygous for 1 of the mutations. The older brother had poor growth, lactic acidosis, and hypertrophic cardiomyopathy resulting in death at age 6 months. The younger brother had hypotonia, poor growth, lactic acidosis, hearing impairment, and hypertrophic cardiomyopathy. He showed developmental delay at age 2 years, 10 months. Biochemical studies of the older brother showed decreased complex I activity (50% of controls) in skeletal muscle, and accumulation of unprocessed mt-tRNA intermediates in muscle and fibroblasts that could be rescued by expression of wildtype ELAC2. Analysis of the mitochondrial transcriptome showed normal levels of mature mt-tRNA, mt-rRNA, and mt-mRNA, but reduced synthesis of mtDNA-encoded OXPHOS components, consistent with a defect in mitochondrial translation. Studies in yeast confirmed that the T520I mutation caused defective mitochondrial respiration via impaired mitochondrial translation.
For discussion of the thr520-to-ile (T520I) mutation in the ELAC2 gene that was found in compound heterozygous state in 2 brothers with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440) by Haack et al. (2013), see 605367.0006.
In a girl, born of consanguineous parents of Arab descent, with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440), Haack et al. (2013) identified a homozygous c.460T-C transition in exon 5 of the ELAC2 gene, resulting in a phe154-to-leu (F154L) substitution at a conserved residue in a metallo-beta-lactamase superfamily domain. The mutation was found by exome sequencing and was present at less than 0.2% frequency in 1,846 control exomes and public databases. She presented at age 2 months with poor growth, hypertrophic cardiomyopathy, and lactic acidosis, and died at age 11 months. Biochemical studies showed decreased complex I activity (60% of normal) in skeletal muscle, and there was an accumulation of unprocessed mt-tRNA intermediates in fibroblasts that could be rescued by expression of wildtype ELAC2. Family history revealed that a brother had died of unknown case at age 13 days and a sister had died of dilated hypertrophic cardiomyopathy at age 3 months.
In 2 sisters, born of consanguineous Turkish parents, with combined oxidative phosphorylation deficiency-17 (COXPD17; 615440), Haack et al. (2013) identified a homozygous c.1267C-T transition in exon 14 of the ELAC2 gene, resulting in a leu423-to-phe (L423F) substitution at a conserved residue. Both girls presented at about 5 months of age with psychomotor delay, hypotonia, and hypertrophic cardiomyopathy. One died at age 4 years, 9 months, and the other was alive and mentally handicapped at age 13 years. Biochemical studies showed decreased activity of complex I in skeletal muscle biopsies (82% and 86% of normal, respectively). One girl also had decreased complex IV (78% of normal) activity and low-normal complex II+III activity, whereas the other had low-normal complex II activity. Muscle and fibroblasts from 1 patient showed accumulation of unprocessed mt-tRNA precursors that could be rescued by expression of wildtype ELAC2.
Brzezniak, L. K., Bijata, M., Szczesny, R. J., Stepien, P. P. Involvement of human ELAC2 gene product in 3-prime end processing of mitochondrial tRNAs. RNA Biol. 8: 616-626, 2011. [PubMed: 21593607] [Full Text: https://doi.org/10.4161/rna.8.4.15393]
Camp, N. J., Tavtigian, S. V. Meta-analysis of associations of the ser217-to-leu and ala541-to-thr variants in ELAC2 (HPC2) and prostate cancer. (Letter) Am. J. Hum. Genet. 71: 1475-1478, 2002. [PubMed: 12515253] [Full Text: https://doi.org/10.1086/344516]
Fujiwara, H., Emi, M., Nagai, H., Nishimura, T., Konishi, N., Kubota, Y., Ichikawa, T., Takahashi, S., Shuin, T., Habuchi, T., Ogawa, O., Inoue, K., Skolnick, M. H., Swensen, J., Camp, N. J., Tavtigian, S. V. Association of common missense changes in ELAC2 (HPC2) with prostate cancer in a Japanese case-control series. J. Hum. Genet. 47: 641-648, 2002. [PubMed: 12522685] [Full Text: https://doi.org/10.1007/s100380200099]
Haack, T. B., Kopajtich, R., Freisinger, P., Wieland, T., Rorbach, J., Nicholls, T. J., Baruffini, E., Walther, A., Danhauser, K., Zimmermann, F. A., Husain, R. A., Schum, J., Mundy, H., Ferrero, I., Strom, T. M., Meitinger, T., Taylor, R. W., Minczuk, M., Mayr, J. A., Prokisch, H. ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am. J. Hum. Genet. 93: 211-223, 2013. [PubMed: 23849775] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.006]
Rebbeck, T. R., Walker, A. H., Zeigler-Johnson, C., Weisburg, S., Martin, A.-M., Nathanson, K. L., Wein, A. J., Malkowicz, S. B. Association of HPC2/ELAC2 genotypes and prostate cancer. Am. J. Hum. Genet. 67: 1014-1019, 2000. [PubMed: 10986046] [Full Text: https://doi.org/10.1086/303096]
Rokman, A., Ikonen, T., Mononen, N., Autio, V., Matikainen, M. P., Koivisto, P. A., Tammela, T. L. J., Kallioniemi, O.-P., Schleutker, J. ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer Res. 61: 6038-6041, 2001. [PubMed: 11507049]
Rossmanith, W. Localization of human RNase Z isoforms: dual nuclear/mitochondrial targeting of the ELAC2 gene product by alternative translation initiation. PLoS ONE 6: e19152, 2011. Note: Electronic Article. [PubMed: 21559454] [Full Text: https://doi.org/10.1371/journal.pone.0019152]
Shea, P. R., Ferrell, R. E., Patrick, A. L., Kuller, L. H., Bunker, C. H. ELAC2 and prostate cancer risk in Afro-Caribbeans of Tobago. Hum. Genet. 111: 398-400, 2002. [PubMed: 12384782] [Full Text: https://doi.org/10.1007/s00439-002-0816-1]
Tavtigian, S. V., Simard, J., Labrie, F., Skolnick, M. H., Neuhausen, S. L., Rommens, J., Cannon-Albright, L. A. A strong candidate prostate cancer predisposition gene at chromosome 17p. (Abstract) Am. J. Hum. Genet. 67 (suppl.): 11 only, 2000. [PubMed: 10848491] [Full Text: https://doi.org/10.1086/302985]
Tavtigian, S. V., Simard, J., Teng, D. H. F., Abtin, V., Baumgard, M., Beck, A., Camp, N. J., Carillo, A. R., Chen, Y., Dayananth, P., Desrochers, M., Dumont, M., and 31 others. A candidate prostate cancer susceptibility gene at chromosome 17p. Nature Genet. 27: 172-180, 2001. [PubMed: 11175785] [Full Text: https://doi.org/10.1038/84808]
Vesprini, D., Nam, R. K., Trachtenberg, J., Jewett, M. A. S., Tavtigian, S. V., Emami, M., Ho, M., Toi, A., Narod, S. A. HPC2 variants and screen-detected prostate cancer. Am. J. Hum. Genet. 68: 912-917, 2001. [PubMed: 11254449] [Full Text: https://doi.org/10.1086/319502]
Wang, L., McDonnell, S. K., Elkins, D. A., Slager, S. L., Christensen, E., Marks, A. F., Cunningham, J. M., Peterson, B. J., Jacobsen, S. J., Cerhan, J. R., Blute, M. L., Schaid, D. J., Thibodeau, S. N. Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer Res. 61: 6494-6499, 2001. [PubMed: 11522646]
Xu, J., Zheng, S. L., Carpten, J. D., Nupponen, N. N., Robbins, C. M., Mestre, J., Moses, T. Y., Faith, D. A., Kelly, B. D., Isaacs, S. D., Wiley, K. E., Ewing, C. M., Bujnovsky, P, . Chang, B., Bailey-Wilson, J., Bleecker, E. R., Walsh, P. C., Trent, J. M., Meyers, D. A., Isaacs, W. B. Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. Am. J. Hum. Genet. 68: 901-911, 2001. [PubMed: 11254448] [Full Text: https://doi.org/10.1086/319513]