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PubMed2001

Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

Abnormalities, Multiple↗
PubMed1995

Germline mutation of BRCA1 in Japanese breast cancer families.

We analyzed germline mutations of the BRCA1 gene in 18 Japanese breast cancer families and two Japanese breast-ovarian cancer families. In two site-specific breast cancer families, the same mutation was detected; a nonsense mutation at codon 63 encoding a truncated small protein. It was demonstrated that the mutant allele cosegregated with breast cancer patients within a family and was absent in healthy Japanese, suggesting a breast cancer-predisposing allele. The average age at diagnosis was 44 and 55 years in each family with BRCA1 mutation. No bilateral breast cancer patients were present in the BRCA1 mutation-positive families, although five were present in the BRCA1-negative families. No germline mutations of BRCA1 were detected in the two breast-ovarian cancer families examined in this study, although BRCA1 mutation plays a major role in breast-ovarian cancer families in Western countries. Thus, the proportion of families who inherit the mutated BRCA1 allele seems to be small among Japanese breast cancer families and Japanese breast-ovarian cancer families.

Adult↗
PubMed2003

BRCA2 germline mutations in familial pancreatic carcinoma.

BACKGROUND: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. METHODS: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. RESULTS: Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. CONCLUSIONS: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.

Adult↗
PubMed2000

Recurrent germline mutation in MSH2 arises frequently de novo.

INTRODUCTION: An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1994

Radiation induction of germline mutation at a hypervariable mouse minisatellite locus.

Paternal 60Co gamma-irradiation was tested for the induction of germline mutation at the mouse hypervariable minisatellite locus, Ms6hm. Male C3H/HeN mice were exposed to 3 Gy 60Co gamma-ray and mated with C57BL/6N females. Matings were made at 1-7, 15-21 and 71-77 days post-treatment to test spermatozoa, spermatids and spermatogonia stages. Reciprocal crosses were also made with irradiated C57BL/6N males. Southern analysis was carried out on DNA from parents and F1 mice. The paternal mutation frequencies per gamete of the Ms6hm locus were 8.3, 13, 28 and 15% for the C3H/HeN control, exposed spermatozoa, spermatids and spermatogonia stages, respectively. The paternal mutation frequencies per gamete were 7.7% for the C57BL/6N control and 13% for the C57BL/6N exposed spermatozoa stage. The increase in the paternal germline mutation frequency was statistically significant for C3H/HeN spermatids irradiation (p < 0.005). The induced mutation frequencies were of the order of 10(-1), and was too high to be accounted for by the direct action of radiation on the locus. These results suggest the presence of a previously unexpected mechanism of radiation induction of germline mutation. In addition, we demonstrate that the hypervariable minisatellite locus can serve as a sensitive monitor for genetic damages to germline cells.

Animals↗
PubMed2005

Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms.

The utility of immunohistochemistry (IHC) as a screening method for the identification of persons with mutations in the DNA mismatch repair (MMR) genes in hereditary nonpolyposis colorectal cancer (HNPCC) remains to be defined. In this study, we analyzed the value of IHC versus that of microsatellite instability (MSI) testing in predicting mutation status of the MLH1, MSH2, and MSH6 genes in colorectal carcinomas and adenomas, and explored the frequency and significance of immunohistochemical staining variability. The study samples included 83 carcinomas and 29 adenomas derived from 110 patients who had strong family histories of colorectal cancer. Our results showed that IHC correctly predicted MSI status in 76% of the cases with a specificity of 100%. The overall sensitivity of IHC in predicting a germline mutation was 79% (30 of 38) with a specificity of 89% (48 of 54), whereas that of MSI testing was 97% (30 of 31) with a specificity of 83% (35 of 42). Six of 31 analyzable cases that had a disease-causing mutation and exhibited MSI showed normal IHC. The lower sensitivity of IHC was caused mainly by its low sensitivity in detecting MLH1 gene mutation (4 of 9). Coexisting adenomas and carcinomas observed in the same slide (n=12) showed a similar or identical staining pattern for all three proteins. No significant difference was detected in the sensitivity of IHC or MSI in detecting a germline mutation between isolated adenomas and carcinomas. In IHC-positive cases, heterogeneous staining was noted in 30% to 40% of the cases with the three different antibodies, and cytoplasmic staining in 5% to 13%. Weak IHC (defined as positive staining in <10% of the tumor with weak intensity) was noted in 14 tumors: 5 for the MLH1 antibody, 1 for MSH2, and 8 for MSH6. One of the 5 MLH1 cases exhibited MSI and had an MLH1 germline mutation. Five of the 8 MSH6 cases exhibited MSI and had MSH2 germline mutations. In conclusion, our study shows that 1) IHC identifies a significant portion of colorectal tumors derived from MMR gene germline mutation carriers and can be used as an adjunct measure in the identification of HNPCC families, but IHC cannot replace MSI testing; 2) adenomas have similar MMR protein expression patterns as carcinomas and may serve as an adequate sample for screening purposes in the identification of patients with MMR mutations; 3) not all IHC-positive cases show uniform positivity throughout the tumor; and 4) weak and focal staining of an MMR protein may be associated with MSI or gene mutation or both, suggesting the need to incorporate staining intensity in further IHC studies.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Prevalence of germline mutations in the TSH receptor gene as a cause of juvenile thyrotoxicosis.

AIM: To ascertain the prevalence of germline mutations in the TSH receptor gene as a cause of juvenile thyrotoxicosis (JT) in non-autoimmune patients. TSH receptor gene mutations are not seen in autoimmune-active patients. METHODS: In a nationwide study on JT, 123 patients were re-examined 10 y (range 4 to 21 y) after diagnosis. Two patients with toxic adenoma were excluded. In 25 patients, no TPO, TG or TSH-R antibodies were found. In 17 patients, DNA material was available for TSH receptor gene analysis. The entire TSH receptor gene was sequenced in five patients. TSH receptor "hot spots" for mutations in exon 9 and 10 were sequenced in the remaining 12 patients. RESULTS: A TSH receptor gene germline mutation was identified in only one patient of a total number of 121 patients with JT, of which 17 patients were presumed to have non-autoimmune JT by the lack of thyroid autoantibodies. CONCLUSION: In Denmark the prevalence of germline mutations in the TSH receptor gene is one in 121 patients with JT (0.8%; 95% CI: 0.02-4.6%) and one in 17 patients with presumed non-autoimmune JT (6%; 95% CI: 5.88% (0.15-28.69)).

Adolescent↗
PubMed2005

Increased risk of cancer in patients with fumarate hydratase germline mutation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

Adolescent↗
PubMedDate not supplied

RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed?

OBJECTIVE: To describe a kindred with a rare RET germline mutation in codon 791 and discuss potential management strategies. METHODS: We present clinical and biochemical data as well as results of mutation analysis in our study subjects and provide an overview of related published reports. RESULTS: Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia or adenoma. Germline mutations in RET are responsible for this autosomal dominant syndrome. Familial MTC is a variant of MEN 2A and can be caused by RET mutations in codon 791. Deaths from gene carriers with mutations in these codons have not yet been reported. In general, gene carriers with these RET mutations have late-onset MTC. Because only a few kindreds with this specific mutation have been identified and no long-term follow-up data are available, management of these patients can be a challenge. We illustrate the difficulties with decisions about not only when to perform thyroidectomy in these patients but also whether thyroidectomy should even be considered in such gene carriers with a benign course. Our reported kindred included four carriers with a codon 791 RET germline mutation, one of whom had the rare concomitant occurrence of acromegaly and MEN 2A. The 70-year-old mother had acromegaly and hyperparathyroidism but normal serum calcitonin levels and normal findings on thyroid ultrasound examination. She refused pentagastrin testing and any surgical intervention. The 37-year-old daughter had hypothyroidism, a small thyroid gland, and negative results of pentagastrin stimulation testing of calcitonin. The 18-year-old grandson also had a negative pentagastrin test result and normal thyroid ultrasound findings. The 5-year-old granddaughter had normal results of thyroid ultrasonography. In all patients, we recommended thyroidectomy. CONCLUSION: Prospective studies are needed to clarify which patients with codon 791 RET germline mutation should undergo thyroidectomy.

Acromegaly↗
PubMed2006

Germline mutations of the PTCH gene in families with odontogenic keratocysts and nevoid basal cell carcinoma syndrome.

BACKGROUND/AIMS: Odontogenic keratocysts (OKC) are aggressive lesions in the jaws, which can occur as isolated cases or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations on PTCH gene have been identified in patients with NBCCS. It was hypothesized that PTCH mutations may be causative in isolated OKC. This study aims to investigate germline mutations of PTCH in families with OKC and NBCCS. METHODS: Three Chinese families with OKC and NBCCS were enrolled in the study. The diagnosis was based on examination and medical history. Mutation analysis was performed by amplifying all exons of PTCH and sequencing the products. RESULTS: One family with isolated OKC (family 1) and the other two families with NBCCS were diagnosed. Three novel germline mutations in PTCH were identified, including a missense mutation (p.S1089 > P) in family 1, a nonsense mutation (p.Q160X) in family 2 and a de novo mutation (c.768_777delGACAAACTTC) in family 3. CONCLUSIONS: It is proposed that isolated OKC can be inherited in an autosomal dominant mode. The results suggest that germline mutations on PTCH can cause isolated OKC, and that the PTCH gene responsible for NBCCS plays an important role in the formation of OKCs even when they are not syndrome-related.

Adult↗
PubMed2004

BRCA2 germline mutations in primary cancer of the fallopian tube.

Germline mutations of BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. It has been recently reported that BRCA1/2 mutations may also predispose to fallopian tube cancer. We report the presence of germline BRCA2 gene mutations in three out of four subjects with fallopian tube cancer diagnosed in a two-year time span at our clinic. The mothers of two of these women suffered from breast or ovarian carcinoma. These results suggest on one hand that in patients with a history suggestive for a heredofamilial breast/ovarian cancer syndrome fallopian tube carcinoma is associated with high risk of BRCA2 mutation, and on the other hand that in patients/individuals with germline BRCA2 gene mutations in whom a prophylactic oophorectomy is performed, removal of fallopian tubes may be considered.

Age Factors↗
PubMed1999

Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests.

Chromosomes, Human, Pair 11↗
PubMed1998

[Germline mutation analysis in hMLH 1 and hMSH 2 genes in hereditary nonpolyposis colorectal cancer and colorectal cancer patients with familial history].

OBJECTIVE: Analysis for germline mutation in mismatch repair genes, hMLH1 and hMSH2, in hereditary nonpolyposis colorectal cancer (HNPCC) patients and presymptomatic diagnosis in HNPCC families. METHODS: Genomic DNA extracted from peripheral blood were subjected to mutation analysis in 35 exons of the hMLH1 and hMSH2 genes by heteroduplex and single strand conformation polymorphism(SSCP) followed by DNA sequencing of aberrant bands in 14 HNPCC and 10 colorectal cancer patients with familial history. RESULTS: Germline mutations were identified in 4/14 HNPCC patients and in 1/10 colorectal cancer patients with familial history, 2 of them in the hMLH1 and 3 in hMSH2 genes. The five mutations are all unique and are predicted to result in nonfunctional proteins by either frameshift (three), nonsense (one) or missense mutation (one) in evolutionarily conserved region. CONCLUSION: HNPPC is closely related to the mutations of mismatch repair genes. Germline mutation analysis for presymptomatic diagnosis in HNPCC could not be limited in the patients meeting clinical diagnosis criteria (Amsterdam 1991).

Adaptor Proteins, Signal Transducing↗
PubMed2000

Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.

BACKGROUND: Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. OBJECTIVE: To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. DESIGN AND METHODS: We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. SETTING: Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. PARTICIPANTS: Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. MAIN OUTCOME MEASURES: The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. RESULTS: Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. CONCLUSIONS: Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

BRCA2 germline mutations in Swedish breast cancer families.

Mutations in the breast cancer susceptibility gene (BRCA2) are believed to be responsible for a significant fraction of hereditary breast cancer. To determine the BRCA2 mutation spectrum in a subset of Swedish breast cancer families, 162 families were screened for germline mutations in this gene. A combination of RT-PCR, PTT and direct DNA sequencing was used. Two mutations and one previously reported polymorphic variant resulting in a truncated protein were identified. Our data suggest that only a small proportion of Swedish breast cancer families is attributable to BRCA2 germline mutations. This result, in combination with the low frequency of BRCA1 germline mutations identified in our previous study, suggests additional high penetrant as well as low penetrant breast cancer susceptibility genes are involved in familial breast cancer.

BRCA2 Protein↗
PubMed2000

Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients.

Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation, with an increased risk for various neoplasms, including gastrointestinal cancer. Recently, the PJS gene encoding the serine/threonine kinase STK11 (also named LKB1) was mapped to chromosome 19p13.3, and germline mutations were identified in PJS patients. We screened a total of ten Korean PJS patients (nine sporadic cases and one familial case including two patients) to investigate the germline mutations of the STK11 gene. By polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing analysis, three kinds of mis-sense mutation and a frame-shift mutation were identified: codon 232 (TCC to CCC) in exon 5, codon 256 (GAA to GCA) in exon 6, codon 324 (CCG to CTG) in exon 8, and a guanine insertion at codon 342 resulting in a premature stop codon in exon 8. These mis-sense variants were not detected in 100 control DNA samples. Furthermore, we found an intronic mutation at the dinucleotide sequence of a splice-acceptor site: a one base substitution from AG to CG in intron 1, which may cause aberrant splicing. Most reported germline mutations of the STK11 gene in PJS patients were frame-shift or non-sense mutations resulting in truncated proteins. Together, these findings indicate that germline mis-sense mutations of the STK11 gene are found in PJS patients in addition to truncating mutations. The effects of these mutations on protein function require further examination. In summary, we found germline mutations of the STK11 gene in five out of ten Korean PJS patients.

AMP-Activated Protein Kinase Kinases↗
PubMed2001

Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes.

The molecular aetiology of Proteus syndrome (PS) remains elusive. Germline mutations in PTEN cause Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are hereditary hamartoma syndromes. Some features-eg, macrocephaly, lipomatosis, and vascular malformations-can be seen in all three syndromes. We examined PTEN in patients with PS and undefined Proteus-like syndromes (PS-like) and identified de-novo germline mutations in two of nine patients with PS and three of five patients with PS-like. Germline PTEN mutation analysis should be done in individuals with PS and PS-like because of its association with increased risk of cancer development and potential of germline-mutation transmission.

Genes, Tumor Suppressor↗
PubMed2006

Radiation-induced untargeted germline mutations in Japanese medaka.

Radiation has been shown to increase mutation frequencies at tandem repeat loci by indirect interactions of radiation with DNA. We studied germline mutations in chronically exposed Japanese medaka (Oryzias latipes) using microsatellite loci. After screening 26 randomly selected loci among unirradiated parents and their 200 offspring, we selected seven highly mutable loci (0.5-1.0 x 10(-2) mutants per locus per gamete) and two bonus loci for further study. To determine if radiation exposure increases mutation frequencies in these loci, medaka were chronically irradiated from subadults through maturation at relatively low dose rates of 68 mGy/d. Total doses for males and females were 10.4 and 3 Gy, respectively. The mean number of mutations for the offspring of exposed families (0.149+/-0.044) was significantly higher (P=0.018) than for control families (0.080+/-0.028), indicating induction of germline mutations from chronic irradiation. This increase in the microsatellite mutation rate is greater than expected from direct interaction of radiation with DNA, suggesting indirect, untargeted mechanism(s) for mutations. This study identified microsatellite loci with a high mutational background in medaka, variation among loci and families as important variables, and demonstrated the usefulness of this fish model for studying radiation-induced germline mutations.

Alleles↗