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PubMed2001

Overexpression of p53 and absent genetic mutation in clear cell chondrosarcoma.

Clear cell chondrosarcoma is one of the extremely rare chondrosarcomas. The pathogenesis and the molecular genetic events, which contribute to the development of clear cell chondrosarcoma, are not well elucidated, due in part to the lack of sufficient tumor tissue available. To characterize the involvement of the p53 gene abnormality in this disease, we analyzed expression and sequence alteration of p53 by immunohistochemical analysis of the protein expression and quantitative DNA/PCR and PCR-SSCP assays of the gene in 28 paraffin-embedded tissue specimens. Immunohistochemical analysis demonstrated that 7 (25%) showed patchy positive nuclear staining for p53 and 5 (18%) showed diffuse positive nuclear staining patterns. Sixteen (57%) were negative for p53 immunostaining. Quantitative DNA/PCR analysis revealed that none of the cases we studied showed significantly reduced levels of p53 amplification (<0.50), strongly suggesting an allelic deletion of the p53 gene. In contrast, however, DNA/PCR-SSCP analysis failed to detect any types of mutations resulting in amino acid substitution within exons 5-9 regions of the gene. Taken together, our data suggest that genetic alteration of p53 is a relatively rare event in clear cell chondrosarcomas but a substantial fraction of this type of tumors carries abnormal overexpression of p53, which might result from an as yet unidentified mechanism(s).

Chondrosarcoma↗
PubMed2005

Evaluation of the interactions of common genetic mutations in stroke.

Stroke is a common entity. It is the third leading cause of death and the leading cause of adult disability in the developed world. More than 110 heritable disorders, more than 175 genetic loci, and more than 2050 unique mutations predisposing to stroke are known. Although ischemic stroke can result from merely one gene defect (and a number of clearly defined mendelian hereditary disorders do lead to stroke), the interaction of unfavorable genetic factors such as the Leiden V, methylenetetrahydrofolate reductase (MTHFR) 677TT, apolipoprotein E (ApoE) 4, and angiotensin-converting enzyme (ACE) D/D genotypes, which alone are not major risk factors, can in specific patterns exert a synergistic effect on certain clinical risk factors. This chapter discusses how to evaluate these interactions and the interpretation of findings.

Apolipoproteins E↗
PubMed1998

Genetic mutations resulting in estrogen insufficiency in the male.

The biosynthesis of estrogens is catalyzed by an enzyme known as aromatase (aromatase cytochrome P450; P450 arom; the product of the CYP19 gene). In recent years a number of patients have been described suffering from aromatase deficiency due to mutations in the CYP19 gene, resulting in the synthesis of a non-functional gene product and a resulting failure to synthesize estrogens. Males with this condition have sustained linear growth into adulthood resulting from failure of epiphyseal closure. Osteopenia and reduced bone mineral density and bone age are also characteristic. Lack of circulating estrogens is accompanied by elevated testosterone and gonadotropins. One of the men had macroorchidism with testicular volumes in excess of 25 ml (Morishima et al. J. Clin. Endocrinol. Metab. 80, 3689, 1995). Semen analysis was not performed on this patient, but it is of note that the one patient described with estrogen insensitivity due to a mutation in the estrogen receptor had a normal sperm count, although motility was decreased (Smith et al., New England J. Med. 331. 1056, 1994). By contrast, the other man with aromatase deficiency had testicular volumes of only 8 ml per testes, and was infertile. Sperm analysis revealed a count of 1 million/ml with 100% immotile sperm (Carani et al. New England J. Med. 337, 91, 1997). However, his clinical picture is confused by the fact that another male sibling has azoospermia, but has no CYP19 mutation, suggesting that the infertility problem may be due to a second genetic condition in this consanguineous family. Recently mice have been generated in which the aromatase (CYP19) gene and the gene encoding the estrogen receptor-alpha have been inactivated by targeted disruption (ArKO and ERKO mice, respectively). Male ERKO mice are infertile with atrophy of the testes and seminiferous tubule dysmorphogenesis resulting in decreased spermatogenesis and inacive sperm. By contrast the ArKO mice are initially fertile and sire litters of normal size ad frequency, however with advancing age the number of litters sired decreases relative to those of wild type litter ates. In contrast to the ERKO mice, light microscopic analysis of the testes of the ArKO mice reveals no gross morphological abnormalties and the testes are of normal size. Following recent observations that the estrogen receptor-beta isoform is highly expressed in seminiferous epthelium, spermatids and spermatocytes, it is conceivable that the relatively high levels of estrogens present in the ERKO mice can act through the ER-beta to cause infertility by a direct action on the testes. In this context it is well known that administration of high levels of estrogen to men results in infertility. It is apparent that studies of human and mouse models with disruptions of aromatase and the estrogen receptor have as yet failed to clarify the role of estrogens in male fertility and testicular function. Development of an ER-beta knockout mouse, or else a double, or even triple, knockout model, may be required in order to resolve these issues.

Animals↗
PubMed2026

Establishing a genetic mutation panel for predicting malignant transformation of oral leukoplakia: A prospective cohort study.

OBJECTIVE: To investigate somatic mutations in the whole genes of tissue samples from patients with oral leukoplakia (OLK), as the most typical precursor of oral cancer; and identify the specific genes as a mutational panel for predicting OLK malignant transformation. METHODS: A total of 123 consecutive OLK patients with long-term follow-up (median, 73&#xa0;months) were prospectively enrolled, and divided into training set (n&#xa0;=&#xa0;92) and independent test set (n&#xa0;=&#xa0;31) based on chronological order of enrollment. Genomic DNA was isolated from the fresh-frozen biopsy tissues and somatic mutations in all genes were measured by whole-exome sequencing. RESULTS: We constructed a 3-gene (TP53, CASP8, and CYP2B6) mutational panel for risk stratification (any mutation vs. no mutation) of OLK malignant transformation. Kaplan-Meier analysis showed that the prognostic power of the 3-gene panel (log-rank P&#xa0;<&#xa0;0.0001) for risk stratification in malignant progression was better than that of pathological grade in the training and test set, respectively. Multivariate Cox regression analysis revealed that this panel was an independent variable significantly associated with progression in the training (hazard ratio [HR]&#xa0;=&#xa0;8.05; P&#xa0;<&#xa0;0.001) and test set (HR&#xa0;=&#xa0;11.26; P&#xa0;=&#xa0;0.0421), respectively. The area under the curve (AUC) with 95&#xa0;% confidence interval was 0.770 (0.648-0.892) and 0.877 (0.705-1.000) in the training and test set, respectively, for predicting malignant transformation in OLK patients. CONCLUSIONS: We established a 3-gene (TP53, CASP8, and CYP2B6) mutational panel as risk stratification model could effectively predict OLK malignant transformation, outperforming pathological grading-based assessment. Such genetic markers may provide a foundation for developing personalized management strategies.

Humans↗
PubMed1999

A genetic mutation in PPAR gamma is associated with enhanced fat cell differentiation: implications for human obesity.

Human obesity may have genetic causes, but determining the specific genes involved has been difficult. The peroxisome proliferator-activated receptor gamma (PPAR gamma) gene encodes a protein that plays an important role in the differentiation of fat cells. A mutation has been discovered in this gene which leads to a receptor that cannot be inactivated. This mutation, while probably rare, is associated with extreme obesity.

Adipocytes↗
PubMed2018

Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.

Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Using the DISC1/NDE1 and CYFIP1/EIF4E loci as exemplars, we explore the opportunities and challenges of using animal models and human-induced pluripotent stem cell technologies to further understand/treat and potentially reverse the worst consequences of these debilitating disorders.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Animals↗
PubMed2002

Detection of a genetic mutation for myotonia congenita among Miniature Schnauzers and identification of a common carrier ancestor.

OBJECTIVE: To develop a molecular genetic test to detect the mutant skeletal muscle chloride channel (CIC-1) allele that causes myotonia congenita in Miniature Schnauzers and to analyze the relationship of affected and carrier dogs. ANIMALS: 372 Miniature Schnauzers from the United States, Canada, Australia, and Europe that were tested between March 2000 and October 2001. PROCEDURE: The sequence surrounding the mutation in the CIC-1 allele was amplified by use of a unique pair of primers. Polymerase chain reaction (PCR) products were digested with the restriction enzyme Hpy CH4 III and separated on a 6% polyacrylamide gel. Pedigrees from all available carrier and affected dogs were analyzed, and a composite pedigree was established. RESULTS: Enzyme digestion of PCR products of the normal CIC-1 allele resulted in 3 fragments of 175, 135, and 30 bp, whereas PCR products of the mutant allele resulted in fragments of only 175 and 165 bp. Of the 372 Miniature Schnauzers, 292 (78.5%) were normal, 76 (20.4%) were carriers, and 4 (1.1%) were affected (myotonic) dogs. Frequency of the mutant allele was 0.113. Pedigree analysis revealed that a popular sire, documented to be a carrier, was a common ancestor of all carriers and affected dogs. CONCLUSIONS AND CLINICAL RELEVANCE: A PCR-based enzyme digestion DNA test was developed. The mutant allele for this disease is frequent in Miniature Schnauzers that are related to a common carrier ancestor. Breeding dogs should be tested by this specific DNA test to help limit the spread of this deleterious mutation.

Animals↗
PubMedDate not supplied

Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression.

Maple syrup urine disease [MSUD] is a rare inborn error of metabolism inherited as an autosomal recessive trait through mutations in any of three different genes that encode components of the branched chain alpha-ketoacid dehydrogenase [BCKD] complex. In this work, the genotype of affected individuals was correlated with their clinical histories. These individuals were diagnosed and followed in a single centralized clinic, and their molecular genetic characterization was done by one laboratory. Three individuals had mutant alleles in the gene for the E1alpha component, five had mutations in the gene for E1beta, and three had mutations in the gene for E2. The results emphasize the diversity of the molecular and clinical presentations for individuals with MSUD and support the complexity of diseases termed "single gene traits." Of primary importance is early identification of at risk infants through newborn screening programs to minimize many of the complications associated with this protein intolerance. Attention to abnormal neurological signs in the neonate or evidence of neurological decompensation in older infants and children by a centralized medical management team minimizes permanent brain damage and improves survival.

Child↗
PubMed1993

Analysis of a genetic mutation in an electrophoretic variant of the human lactate dehydrogenase-B(H) subunit.

An electrophoretic variant of the lactate dehydrogenase (LDH)-B(H) subunit was discovered in a patient with diabetes mellitus. His LDH activity in serum was slightly lower than normal and the LDH isozyme pattern showed an abnormal migration indicating an LDH-B subunit variant of the fast type. The LDH containing the variant subunit revealed a decreased heat stability. DNA analysis of the variant allele detected a base substitution, an A to G transition, at codon 6 (AAA-->GAA). The mutation resulted in the replacement of a lysine by a glutamic acid (K6E). The change may cause the heat instability and affect the net charge of the variant subunit, resulting in an electrophoretic LDH-B subunit variant of the fast type.

Aged↗
PubMedDate not supplied

Overexpression of p53 and rare genetic mutation in mesenchymal chondrosarcoma.

Mesenchymal chondrosarcoma is extremely rare and accounts for less than 2% of all chondrosarcomas. The pathogenesis and the molecular genetic events which contribute to the development of mesenchymal chondrosarcoma are not well elucidated, due in part to the lack of sufficient tumor tissue available. To characterize the involvement of the p53 gene abnormality in this disease, we analyzed expression and sequence alteration of p53 by immunohistochemical analysis of the protein expression and quantitative DNA/PCR and PCR-SSCP assays of the gene in 33 paraffin-embedded tissue specimens. Immunohistochemical analysis demonstrated that 19 (61.3%) of 31 had nuclear overexpression of p53 while 7 (22.6%) showed cytoplasmic expression. The remaining 5 (16.1%) were negative for p53 staining. The nuclear positivity of p53 was observed within a range of 22-64% (mean 37.3%) of tumor cells and showed a positive staining in mesenchymal components as well as chondroid components. Quantitative DNA/PCR analysis revealed that 6 (18.2%) of the 33 specimens carried significantly reduced or undetectably low levels of p53 indicating the genomic deletion of the gene in these tumors. In contrast, however, DNA/PCR-SSCP analysis failed to detect any types of mutations resulting in amino acid substitution within exons 5-9 regions of the gene. Taken together, our data suggests that genetic alteration of p53 is a relatively rare event in mesenchymal chondrosarcomas but substantial fraction of this type of tumors carries abnormal overexpression of p53, which might result from as yet unidentified epigenetic mechanism(s).

Chondrosarcoma, Mesenchymal↗
PubMed1993

Detection and characterization of new genetic mutations in individuals heterozygous for lactate dehydrogenase-B(H) deficiency using DNA conformation polymorphism analysis and silver staining.

Human lactate dehydrogenase (LDH)--B(H) mutant genes were analyzed by polymerase chain reaction (PCR) and DNA conformation polymorphism. We used polyacrylamide gradient gel and silver staining procedures for DCP analysis, and observed abnormal migration patterns in individuals heterozygous for the LDH-B deficiency. Subsequent sequence determination of the mutant alleles consistently resulted in detection of three single base substitutions (transversions), viz., a C to A at residue "35" (GCG, Ala-->GAG, Glu), a T to G at residue "172" (TTT, Phe-->GTT, Val), and an A to T at residue "176" (ATG, Met-->TTG, Leu). Furthermore, mismatched PCR or amplification refractory mutation system was developed for the rapid screening and confirmation of these mutations. These amino acid replacements may cause conformational changes in neighboring residues; this probably affects the active site arrangement and results in the loss of enzyme activity.

Amino Acid Sequence↗
PubMed1997

Hirschsprung's disease: genetic mutations in mice and men.

Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births. Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven. Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung's disease in humans. Moreover, certain mutant mouse strains--namely piebald lethal and lethal spotted--exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene, and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B. Two transgenic mouse lines have been developed which also reflect the human disease: ret-k-, which has a loss of function mutation of the ret gene, and ENDR-B null. In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by "Hirschsprung's-like" mutations. Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis. This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung's disease. Disruption of these genes in the mouse, either by transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.

Animals↗