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At least 685 records · Page 38Linked to original sources
PubMed1999

Mobilization of two retroelements, ZAM and Idefix, in a novel unstable line of Drosophila melanogaster.

We describe a novel transposition system in a line of Drosophila melanogaster called RevI in which two retroelements are mobilized. These elements are the retroelement ZAM, recently described in the literature, and a novel element designated Idefix. Like ZAM, Idefix displays the structural features of a vertebrate retrovirus. Its three open reading frames encode predicted products resembling the products of the gag, pol, and env genes of retroviruses. In situ hybridization and Southern analyses performed on the RevI genome revealed the presence of some 20 copies of ZAM and Idefix, whereas ZAM is absent and Idefix is present in only four copies on the chromosomal arms of the original parental line. From RevI, a series of mutations affecting eye coloration has been recovered. The genetic and molecular analyses of these mutations have shown that most of them affected the white locus through three rounds of mutational events. The first mutational event was previously shown to be caused by a ZAM insertion 3 kb upstream of the transcription start site of white. It confers a red-brick phenotype to the orange eye coloration of the parental line. The second event results from the insertion of an Idefix copy 1.7 kb upstream of the transcription start site of the white gene, which modifies the red-brick phenotype to orange. This second mutational event was recovered as a recurrent specific mutation in 11 independent individuals. The third event results from an additional Idefix located 1.7 kb upstream of white that is responsible for the full reversion of the orange phenotype to red-brick. The fact that such mutations due to recurrent appearances of both ZAM and Idefix at the white locus result in such a variety of phenotypes brings to light a new molecular system in which the interference of mobile elements with the correct expression of the host gene can be tested.

Alleles↗
PubMed2006

Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia.

Two recurrent missense mutations (c.20C>T: A7V; c.26C>T: A9V) in the gene encoding the myofibrillogenesis regulator 1 (MR-1) have been shown to cause autosomal dominant paroxysmal nonkinesigenic dyskinesia (PNKD) in 13 families of primarily European ancestry. Here we report an Omani PNKD family with seven affected family members and autosomal dominant inheritance. Our linkage analysis provided consistent positional evidence that the MR-1 gene could be the responsible disease gene. Sequence analysis identified a MR-1 missense mutation (c.20C>T; A7V) in the affected family members, whereas it was not present in five unaffected family members and 129 population controls. Taking into account that previous haplotype analyses did not reveal evidence for common founders among several PNKD families, our present findings strengthen three implications: (1) autosomal dominant PNKD seems to be a homogenous disorder, for which the MR-1 gene is the major disease gene; (2) mainly two recurrent MR-1 missense mutations (57% V7, 43% V9) account for the genetic variance of familial PNKD; (3) it supports current evidence that some of the recurrent MR-1 mutations may have arisen independently by de novo mutation at functionally convergent key sites of the brain-specific MR-1L isoform.

Chorea↗
PubMed1998

A novel mutation (V191G) in a German-British type 1 Gaucher disease patient. Mutations in brief no. 131. Online.

Gaucher disease results from mutations in the glucocerebrosidase gene located on human chromosome 1q21. Three clinical forms of Gaucher disease have been described: type 1, nonneuropathic; type 2, acute neuropathic; and type 3, subacute neuropathic. We have identified a novel mutation in a German-British patient with type 1 Gaucher disease which results in V191G of the glucocerebrosidase polypeptide. Because the mutation abolishes a HphI cleavage site, its presence was confirmed by HphI RFLP analysis of PCR-amplified genomic DNA. In the second allele of the patient, the mutation identified was g.5841A G(N370S). Sequence analysis of the remainder of the coding region of the gene as well as the exon-intron boundaries showed identity to normal controls. Because mutation N370S has so far been found only in type 1 Gaucher disease and postulated to result in mild clinical presentation, and since the clinical course of this patient has been relatively mild with minimal skeletal involvement, we speculate that the V191G/N370S genotype may also result in good prognosis.

Chromosomes, Human, Pair 1↗
PubMed2000

A novel mutation detected by temporal temperature gradient gel electrophoresis led to the confirmative prenatal diagnosis of a Hispanic CF family.

Mutational analysis of 30 recurrent known mutations detects only about 58% of Hispanic cystic fibrosis (CF) chromosomes. The low mutation detection rate has greatly hindered prenatal diagnosis and carrier testing of Hispanic families who have multiple affected children with unidentified cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We recently employed a temporal temperature gradient gel electrophoresis (TTGE) method to effectively scan unknown mutations in the entire CFTR gene. A novel mutation, 2105-2117 del13insAGAAA was identified in a Hispanic family heterozygous for delta F508. The discovery of the devastating mutation facilitated the prenatal diagnosis for this family who already had two severely affected children. The fetus was found to be a compound heterozygote of delta F508/2105-2117 del13insAGAAA. This case emphasizes the importance of whole gene mutational analysis in patients with a clinical diagnosis of CF, but without the identifiable DNA mutations by routine mutation analysis. Finding of CF mutations in the patient would allow proper genetic counselling and prenatal and carrier detection of at-risk family members.

Adolescent↗
PubMed2000

Recurrent fallopian tube carcinoma: TP53 mutation and clinical course.

Primary fallopian tube carcinoma is a rare, aggressive gynecological cancer; little is known about its cause. Previous studies have indicated that p53 immunopositivity is correlated with short-term survival in primary fallopian tube carcinoma. We examined p53 and p21/WAF1 immunostaining and TP53 mutation in exons 5 to 8 by single-stranded conformation polymorphism and constant denaturant gel electrophoresis in nine cases of primary fallopian tube carcinoma and their metastases/recurrences from patients who survived for between a few months and more than 20 years after diagnosis. We found that 1.) p53 immunopositivity without detectable p21/WAF1 immunostaining did not correlate with TP53 mutations in the conserved domains; 2.) mutations in TP53 occurred in two metastases/recurrences but not in their corresponding primary tumors; 3.) in two cancers, a TP53 mutation was observed in the primary tumor but not in the metastases/recurrences; 4.) constant denaturant gel electrophoresis seems to be more sensitive than single-stranded conformation polymorphism in detecting TP53 mutations; and 5.) in the nine cases studied, p53 immunoreactivity and/or TP53 mutation analysis did not correlate with tumor progression, survival, or response to treatment.

Aged↗
PubMed2026

To Treat or Not to Treat: Navigating Early-Stage CLL in the Era of Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.

Humans↗
PubMed2004

An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia.

Anorchia, or the "vanishing testis syndrome," is characterized by the absence of testis in a 46,XY individual with a male phenotype. The etiology is unknown; however, the familial occurrence of the disease and the association of this phenotype with 46,XY gonadal dysgenesis has led to the suggestion that genetic factors, which play a role in testicular determination, may be involved. Alternatively, exploratory laparoscopy has suggested that anorchia may be caused by a prenatal testicular vascular accident associated with torsion during testicular descent. We screened a cohort of 14 boys with bilateral anorchia for mutations in the Y chromosome-linked testis-determining gene SRY (sex-determining region, Y chromosome); in the gene necessary for correct testicular descent, INSL3; and in the gene of its receptor (LGR8). Mutations in the INSL3 gene and the LGR8 T222P mutation are known to cause cryptorchidism. We confirmed previous reports that mutations in the SRY gene are not associated with anorchia. Although a common polymorphism was identified in the INSL3 gene, no mutations were observed. The recurrent T222P mutation in the LGR8 gene was not found in any of the patients. These data show for the first time a lack of association between genetic factors necessary for correct testicular descent and anorchia.

Adolescent↗
PubMed2000

Achondroplasia in diverse Jewish and Arab populations in Israel: clinical and molecular characterization.

BACKGROUND: Achondroplasia is the most frequent form of disproportionate short stature, characterized by rhizomelic shortening of the limbs. This disorder is inherited as an autosomal dominant trait, although most of the cases are sporadic, a result of a de novo mutation. A recurrent glycine to arginine mutation at codon 380 (G380R) in the transmembrane domain of the fibroblast growth factor receptor 3 gene was found to cause achondroplasia among different populations. This is most uncommon in other autosomal dominant genetic diseases. OBJECTIVES: To determine whether this mutation is also common among Jewish patients from diverse ethnic groups and among the Arab population in Israel. METHODS: We examined the G380R mutation (G > A and G > C transition) and the mutation G375C (G > T transition at codon 375) in 31 sporadic patients and in one family diagnosed clinically to have achondroplasia. RESULTS: We found the G > A transition at codon 380 in 30 of our patients and the G > C transition in one patient. We were not able to detect any of the three mutations in two patients with an atypical form of achondroplasia. CONCLUSIONS: Our results further support the unusual observation that nucleotide 1138 of the FGFR3 gene is the most mutable nucleotide discovered to date across different populations.

Achondroplasia↗
PubMed2000

Effect of heterozygosity for the methionine synthase 2756 A-->G mutation on the risk for recurrent cardiovascular events.

Increased dietary intake of folate has been shown to significantly reduce the risk for fatal myocardial infarction, possibly by lowering homocysteine levels. We therefore investigated the association between recurrent cardiovascular events and a mutation in methionine synthase (2756 A-->G)--an enzyme directly involved in folate and homocysteine metabolism. This mutation significantly reduced the risk for recurrent cardiovascular events and elevated red blood cell folate levels.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2006

Recurrent KRAS codon 146 mutations in human colorectal cancer.

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.

Adenocarcinoma↗
PubMed2026

Hepatocellular Carcinoma With JAK1 Mutations Harbors Distinct Histologic Features and Specific Mutational Hotspots in an Asian Cohort.

The pathogenesis and clinicopathological features of hepatocellular carcinoma (HCC) harboring JAK1 mutation have not been reported. Sixty inflammatory hepatocellular adenoma-like HCCs (IHA-like HCCs) and 16 IHAs were analyzed using targeted next-generation sequencing. Nearly all IHA-like HCCs (n=59, 98%) showed positive SAA/CRP expression. Genetic alterations of the JAK/STAT pathway were detected in 35 (58%) IHA-like HCCs, encompassing mutations in JAK1 (n=22), STAT3 (n=8), and IL6ST (n=5). Nine (56%) IHAs harbored mutations in STAT3 (n=3), IL6ST (n=4), GNAS (n=1), and FRK (n=1). All the mutations occurred in a mutually exclusive manner. JAK1 mutations were frequent (22/60, 37%) in IHA-like HCCs. JAK1-mutated IHA-like HCCs displayed distinctive cytologic characteristics, including abundant eosinophilic cytoplasm, vesicular chromatin, and prominent central nucleoli. Recurrent hotspot JAK1 mutations were identified at S703, S729, and L910. Surveillance for JAK1 mutations in the HCC genomics of other cohorts also revealed recurrent mutations at S703, S729, and L910. In particular, the S703 and S729 mutations were strongly associated with the features of Asian ethnicity, presence of chronic viral hepatitis, and hepatic fibrosis/cirrhosis. In conclusion, JAK1 mutations were frequent in HCC with IHA-like morphology in an Asian cohort. JAK1 mutation exhibited recurrent and specific hotspot mutations at S703, S729, and L910 in HCC. Patients diagnosed with JAK1-mutated HCC may be eligible for JAK-targeted molecular therapy.

JAK therapeutics↗
PubMed1999

The factor V Leiden mutation in Japanese couples with recurrent spontaneous abortion.

Thrombosis of placental vessels can be a major cause of recurrent spontaneous abortion (RSA). The factor V Leiden (FVL) mutation, a single point mutation in the factor V gene, is the most common genetic predisposition to thrombosis in European countries and the United States. However, even among Caucasian populations, the association between the FVL mutation and RSA is still controversial. The objectives of the present study were to investigate the prevalence of the FVL mutation in Japanese women who have experienced RSA and to clarify the contribution of the FVL mutation to recurrent miscarriages. A total of 52 Japanese women with a history of three or more consecutive idiopathic first trimester miscarriages and 41 of their male partners were studied. The control group consisted of 55 parous women without obstetric complications. Peripheral blood cell DNA was examined for the presence of the FVL alleles by polymerase chain reaction with Mnl I restriction fragment length polymorphisms. None of the 52 women with RSA and the 41 partners carried the mutation. We also found no subject carrying the FVL alleles in the control group. These results suggest that the FVL alleles are not concentrated in women with RSA at least to clinically significant levels and that there is no apparent association between the FVL mutation and RSA in our Japanese population.

Abortion, Habitual↗
PubMed2001

G20210A prothrombin gene mutation: prevalence in a recurrent miscarriage population.

Many recurrent pregnancy losses appear to have a thrombotic etiology. We have investigated the prevalence of the G20210A prothrombin gene mutation in 122 women with a history of three or more early (< or = 12 weeks gestation; n = 91), late (> 12 weeks gestation: n = 2), or mixed (n = 29) consecutive pregnancy losses. A control group of 66 healthy parous women with no history of thrombosis or miscarriage was also studied. Four heterozygotes that suffered only early pregnancy losses were detected in the patient group giving a prevalence of 3.3%. Three of the control group women were heterozygous for the mutation. giving a prevalence of 4.5% (p = 0.32: odds ratio 0.71: 95% confidence interval [CI] 0.15-3.27). When only Caucasians were analyzed, a prevalence of 3.9% (4/103) was observed in the patient group and 4.2% (2/48) in the control group (p = 0.28; odds ratio 0.89; 95% CI 0.16-5.05). The prevalence of the G20210A prothrombin gene mutation is not increased in women with recurrent miscarriage, although it was only found in women who had suffered early pregnancy losses. However, it remains possible that this mutation is relevant in a selected subgroup of women with recurrent miscarriage, additional thrombophilic defects, and in whom fetal loss is associated with placental infarction and thrombosis.

Abortion, Habitual↗
PubMed2003

Mutation of p53 in recurrent hepatocellular carcinoma and its association with the expression of ZBP-89.

p53 has recently been identified as a downstream target of ZBP-89, a zinc finger transcription factor. ZBP-89 promotes growth arrest through stabilization of the p53 protein. The aim of this study is to determine the status of the p53 gene in recurrent human hepatocellular carcinoma (HCC) and test the link between the expression of ZBP-89 and the p53 gene. The results showed that mutations in the p53 gene were frequently detected in recurrent HCC. The interval between surgical resection and the recurrence of HCC was significantly longer in patients with the wild-type p53 gene than those with mutations, strongly suggesting a pathological role for the mutant p53 gene in HCC recurrence. Among those positive for the p53 protein, nearly 85% (18 of 21) showed nuclear localization of the p53 protein while only about 14% (3 of 21) were positive for the p53 protein in the cytoplasm. ZBP-89 co-localized with p53 in the nucleus in about 67% (12 of 18) of all cases positive for the nuclear p53 protein, suggesting that ZBP-89 may play a role in the nuclear accumulation of the p53 protein in a subset of recurrent HCC. With accumulation of p53 protein in the nucleus, tumor cells undergo apoptosis and thus are more susceptible to radiotherapy and chemotherapy. Therefore, co-localization of p53 protein with ZBP-89 may define a subgroup of recurrent HCC that is more sensitive to treatment.

Adult↗
PubMed1997

Recurrent ovarian cyst and mutation of the Gs alpha gene in ovarian cyst fluid cells: what is the link with McCune-Albright syndrome?

Isolated peripheral precocious puberty due to recurrent ovarian cysts evokes a McCune-Albright syndrome (MAS). This syndrome associates endocrine dysfunction such as precocious puberty, polyostotic fibrous dysplasia, and "café-au-lait" skin lesions. We report the case of a 3-y-old girl who presented with peripheral puberty with extremely elevated oestradiol level, low LH and FSH levels, and an ovarian cyst that quickly resolved. Skeletal X-rays were normal and she had no café-au-lait spots. GnRH analogue treatment was ineffective. A second ovarian cyst appeared and was completely drained under ultrasonographic guidance. Molecular biological analysis performed on fluid cells revealed the Arg201-->His mutation of the Gs alpha gene described in MAS. Percutaneous aspiration of simple ovarian cyst to detect "MAS" mutation is of interest in the diagnosis of recurrent ovarian cyst.

Child, Preschool↗
PubMed2000

Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland.

Germline mutations in the BRCA1 and BRCA2 genes account for the majority of high-risk breast/ovarian cancer families, depending on the population studied. Previously, BRCA1 mutations were described in women from Western Poland. To further characterize the spectrum of BRCA1 mutations and the impact of BRCA2 mutations in Poland, we have analyzed 25 high-risk breast and/or ovarian cancer families from North-Eastern Poland for mutations in all coding exons of the BRCA1 and BRCA2 genes, using combined heteroduplex analysis/SSCP followed by direct DNA sequence analysis. Out of 25 probands a total of five (20%) carried three recurrent BRCA1 mutations (300T>G, 3819del5, 5382insC). The 300T>G mutation accounted for 60% (3/5) of BRCA1 mutations and allelotyping suggested a common founder of this mutation. No unique mutations were found. In addition, we identified three BRCA2 (12%) mutations, one recurrent 4075delGT, and two novel frameshift mutations, 7327ins/dupl19 and 9068delA. We conclude that 30% of high-risk families from North-Eastern Poland may be due to recurrent BRCA1 and unique BRCA2 mutations. Intriguingly, the BRCA1 mutation spectrum seems to be different within subregions of Poland.

Adult↗
PubMed2000

Alteration of a p53 gene status affects outcome of patients with recurrent ovarian cancer.

The aim of this longitudinal study was to examine whether and how the p53 gene is altered in patients with recurrent ovarian cancer and to determine the significance of p53 mutation in recurrent tumors. The primary and recurrent tumors were examined in 15 patients who had recurrent epithelial ovarian cancer, and whose primary tumor contained a wild-type p53 gene. The interval between cytoreductive surgery and the appearance of recurrence ranged from 5. 2 to 63.6 months (mean 23.4 months). Mutations in the p53 gene were screened by polymerase chain reaction single strand conformation polymorphism analysis and determined by cycle sequencing. Mutation of the p53 gene in the recurrent tumor was found in 7 of the 15 patients (46.7%). Estimated 3- and 5-year survival rates were 57.1 and 0%, respectively, for patients with p53 gene mutation detected in the recurrence tumor, and 75.0% and 37.5% for patients without the mutation (p = 0.0155). The interval between cytoreductive surgery and the appearance of recurrence did not differ between those groups (549.7 +/- 102.2 vs. 832.9 +/- 283.8 days). Mean survival time after recurrence was significantly better in the patients without mutation (438.6 +/- 56.4 vs. 873.0 +/- 157.5 days, p = 0.0125). The present study suggests that p53 gene mutation frequently occurs in recurrent ovarian cancer and that alteration of p53 gene status affects salvage chemotherapy. This phenomenon affects the prognosis of recurrent disease and may predict outcome.

Aged↗
PubMed1995

Recurrence of the R408W mutation in the phenylalanine hydroxylase locus in Europeans.

The relative frequency of the common phenylalanine hydroxylase (PAH) mutation R408W and its associations with polymorphic RFLP, VNTR, and short-tandem-repeat (STR) sites in the PAH gene were examined in many European populations and one representative North American population of defined European descent. This mutation was found to cluster in two regions: in northwest Europe among Irish and Scottish peoples, and in eastern Europe, including the Commonwealth of Independent States. This allele was significantly less frequent in intervening populations. In eastern European populations, the R408W mutation is strongly associated with RFLP haplotype 2, the three-copy VNTR allele (VNTR 3), and the 240-bp STR allele. In northwestern European populations, it is strongly associated with RFLP haplotype 1, the VNTR allele containing eight repeats (VNTR 8), and the 244-bp STR allele. An examination of the linkage between the R408W mutation and highly polymorphic RFLP, VNTR, and STR haplotypes suggests that recurrence is the most likely mechanism to account for the two different major haplotype associations of R408W in Europe.

Alleles↗