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Results for “deleterious mutation”

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PubMed2001

Genetic susceptibility for breast cancer--risk assessment and counseling.

The incorporation of genetic information into clinical oncology practice is a process in evolution, necessitating consideration of cancer risk assessment, ethical and social implications of testing and efficacy of treatment, and prevention interventions. Although most cancers do have a hereditary component, recognizing individuals who are at unusually high risk is important for planning their surveillance practices and considering options for risk management over a lifetime, and because of implications for their family members. Genetic information has enormous potential to inform and transform cancer risk identification, risk reduction, and treatment practices. In this review, we summarize basic information about breast cancer genetics, examine accumulating data about the prevalence and penetrance of deleterious mutations and management options for BRCA1 and BRCA2 mutation carriers, and discuss some of the counseling issues that may occur as physicians and patients explore this exploding area of oncology. The rapid incorporation of careful genetic testing into oncology practice is an important step toward more precise risk management. Currently, the time necessary for careful discussion of the complex issues raised by genetic testing for inherited breast/ovarian cancer susceptibility may necessitate referral to geneticists or genetic counselors for truly informed consent to be obtained. However, identification of women for whom testing is appropriate and management of cancer risk with women after testing, are critical new functions for oncologists. They are only the beginning of exciting new opportunities in cancer risk and prevention.

BRCA2 Protein↗

PubMed1984

Characterisation and use of an intragenic polymorphic marker for detection of carriers of haemophilia B (factor IX deficiency).

DNA from 33 healthy White subjects was analysed with a 2 X 5 kilobase subgenomic DNA probe derived from the gene for coagulation factor IX, containing the exon "d" region of that gene. Intragenic Taq I restriction-fragment length polymorphism was revealed, with allelic frequencies estimated at 0 X 65 and 0 X 35 (SE = 0 X 06), also detectable by a cDNA probe. The genomic DNA probe is technically superior to the cDNA probe and has been used in three families with haemophilia B (factor IX deficiency). The polymorphic marker segregates with the deleterious mutation, allowing the identification or exclusion of carriers. The allelic frequencies of the Taq I polymorphism are virtually ideal. Therefore, such a polymorphism should be helpful both in genetic counselling of approximately 40% of affected families and in prenatal diagnosis.

Alleles↗

PubMed2001

Molecular cloning of mouse allantoicase cDNA.

The uric acid degradation pathway is progressively lost during vertebrate evolution. In mammals, the end product of this catabolic pathway is allantoin and, therefore, no allantoicase should be present in mouse tissues. Surprisingly, we have found an expressed sequence tag (EST) from mouse testis with high similarity to allantoicase. To characterize this transcript, we have completely sequenced the corresponding EST clone insert and found a 1495 bp long cDNA coding for a 414 amino acid long protein. Identities of mouse versus microorganism allantoicases range from 25 to 30%. Identity reaches 54% when compared to Xenopus allantoicase. Among the tested tissues, only testis possesses the allantoicase transcript. Although no deleterious mutations were found in the coding region, no allantoicase activity could be detected in mouse testis.

Amino Acid Sequence↗

PubMed2001

Sex and U.

Resolution of several unsettled problems in genetics depends on the genomic rate of deleterious mutation, U. Selection against mutations can be a major factor in evolution only if U > or =1. Recently, significant progress has been made in measuring U in multicellular eukaryotes. An indirect estimate, based on a human-chimpanzee pseudogene comparison, produced U>3 for hominoids. By contrast, an estimate for Drosophila based on comparison of synonymous protein-coding sites produced U<0.1. However, the Drosophila figure might be underestimated because of selection at synonymous sites. Perhaps, the best way to measure U is to observe mutations shortly after they appear. So far, this direct approach has been applied only to humans and Caenorhabditis elegans, yielding high estimates of mutation rates.

Animals↗

PubMed2000

Natural variation in immune responsiveness, with special reference to immunodeficiency and promoter polymorphism in class II MHC genes.

This review deals with natural selection operating on heterozygotes as a key factor controlling (a) the frequency of immunodeficiencies, and (b) promoter polymorphism in MHC class II genes. The known difference in frequency distribution of X-linked and autosomal deficiencies lend support to this possibility, and suggest that the frequency of neonatal defect may rise as old-established equlibria between entry and exit of deleterious mutations change. MHC class II gene promoters differ in their capacity to favor Th1 (or reciprocally Th2) responses, thus suggesting that promoter polymorphism is sustained by the greater flexibility in response that this confers on heterozygotes.

Animals↗

PubMed2002

The role of vitamin D receptor gene polymorphisms in bone biology.

The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known but the vitamin D endocrine system seems to play an important role in other metabolic pathways as well, such as those involved in osteoarthritis, the immune response and cancer. One approach to understand the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently but their effects are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits such as osteoporosis. The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that several of the polymorphisms used have unknown effects. However, current data indicate that dozens of additional polymorphic variations exist in the VDR gene that could each have different types of consequences. Therefore, efforts are focussed on finding novel sequence variations and to study their interaction in molecular- and cell-biological experiments as well as in genomic epidemiological studies. The ultimate goal of this approach is to identify the combinations of functional sequence variants that modulate the vitamin D endocrine system and confer risk of disease.

Bone and Bones↗

PubMed2000

Neutralism and selectionism: the molecular clock.

The neutrality theory predicts that the rate of molecular evolution will be constant over time, and thus that there is a molecular clock for timing evolutionary events. It has been observed that the variance of the rate of evolution is generally larger than expected according to the neutrality theory. Several modifications of the theory have been proposed to account for the 'overdispersion' of the molecular clock, by postulating effects attributed to generation-time, population size, slightly deleterious mutations, repair mechanisms, and the like. An extensive investigation of two proteins, glycerol-3-phosphate dehydrogenase (GPDH) and superoxide dismutase (SOD), manifests that none of these modifications can simultaneously account for the disparate patterns observed in both proteins. GPDH evolves very slowly in Drosophila species, but several times faster in mammals, other animals, plants, and fungi. SOD evolves very fast in Drosophila species and also in mammals, but much more slowly in other animals and still slower when plants and fungi are compared to one another, or to animals.

Animals↗

PubMed1997

Identification and characterization of a mouse homologue of the spinal muscular atrophy-determining gene, survival motor neuron.

Spinal muscular atrophy (SMA), the second most common fatal, autosomal recessive disease of infants, manifests as generalized muscle weakness. The most severe form (Type I, Werdnig-Hoffmann disease) is associated with quadriplegia, respiratory muscle paralysis and death in infancy. Less severe forms are classified as Type II and Type III, based on age of onset and ultimate motor disability. Some spinal motor neurons show chromatolysis and the number of these cells is decreased. Recently, SMA has been mapped to chromosome 5q11.2-13.3 (Gilliam et al., 1990), a region that contains three candidate genes: Survival Motor Neuron (SMN) (Lefebvre et al., 1995); Neuronal Apoptosis Inhibitory Protein (NAIP) (Roy et al., 1995); and p44, a subunit of transcription factor II H (TFIIH) (Carter et al., 1995; Bürglen et al., 1997). Homozygous deletions or deleterious mutations in SMN are present in all SMA patients, and in some affected individuals, deletions have been identified in one or both of the other genes. These extensive deletions may be associated with a more severe phenotype. We have identified and characterized the mouse homologue of SMN, MoSMN, which is 82% identical to SMN at the amino-acid level. Unlike the duplicated human SMN, MoSMN is present in single copy. Like its human counterpart, MoSMN is ubiquitously expressed, but unlike SMN, MoSMN does not appear to be alternatively spliced. In-situ hybridization analysis of the mouse nervous system revealed that MoSMN mRNA is expressed in spinal cord and throughout the brain, with relatively higher levels of expression in the hippocampus and cerebellum.

Alternative Splicing↗

PubMed2001

Does bristlecone pine senesce?

We evaluated hypotheses of senescence in old trees by comparing putative biomarkers of aging in Great Basin bristlecone pine (Pinus longaeva) ranging in age from 23 to 4713 years. To test a hypothesis that water and nutrient conduction is impaired in old trees we examined cambial products in the xylem and phloem. We found no statistically significant age-related changes in tracheid diameter, or in several other parameters of xylem and phloem related to cambial function. The hypothesis of continuously declining annual shoot growth increments was tested by comparing trees of varying ages in regard to stem unit production and elongation. No statistically significant age-related differences were found. The hypothesis that aging results from an accumulation of deleterious mutations was addressed by comparing pollen viability, seed weight, seed germinability, seedling biomass accumulation, and frequency of putative mutations, in trees of varying ages. None of these parameters had a statistically significant relationship to tree age. Thus, we found no evidence of mutational aging. It appears that the great longevity attained by some Great Basin bristlecone pines is unaccompanied by deterioration of meristem function in embryos, seedlings, or mature trees, an intuitively necessary manifestation of senescence. We conclude that the concept of senescence does not apply to these trees.

Animals↗

PubMed1998

Palmitoyl-protein thioesterase deficiency in a novel granular variant of LINCL.

Typically, late infantile neuronal ceroid-lipofuscinosis (LINCL) patients present between the ages of 2 and 4 years with progressive dementia, blindness, seizures, and motor dysfunction. Curvilinear profiles are seen on electron microscopic examination of tissues derived from those patients. Data were collected on 122 LINCL cases, representing 81 independent families, diagnosed on the basis of age of onset, clinical symptomatology, and pathologic findings. Careful analysis of our data has revealed that 20% of these cases (24 of 122) show either an atypical clinical course or atypical pathologic findings and may represent variants of LINCL. Recent progress in the biochemistry and molecular genetics of NCL has led us to reevaluate these atypical cases. Five atypical LINCL cases (representing three independent families) manifested granular inclusions when examined by electron microscopy, a finding normally associated with the infantile form of NCL. In addition, these five cases did not show elevated subunit c levels in urine (typically seen in LINCL). In these five cases, palmitoyl-protein thioesterase activity was found to be deficient (less than 10% normal activity), suggesting that these cases represent INCL, presenting at a later age of onset. These findings suggest that palmitoyl-protein thioesterase deficiency is not restricted to infantile onset cases, and they raise the possibility that milder forms of INCL may result from less deleterious mutations.

Age of Onset↗

PubMed1993

Human Zn-alpha 2-glycoprotein: complete genomic sequence, identification of a related pseudogene and relationship to class I major histocompatibility complex genes.

The human gene (AZGP1) encoding Zn-alpha 2-glycoprotein (Zn-alpha 2-gp), a protein present in several biological fluids and produced by a subtype of breast carcinomas, has been cloned and its complete nucleotide sequence determined. The gene spans over 9.7 kb, and its overall organization and nucleotide sequence are very similar to those of the first four exons of class I MHC genes. However, the Zn-alpha 2-gp gene differs from these genes in several significant ways. It lacks the coding information for the transmembrane and cytoplasmic domains typical of MHC genes, which is consistent with its presence as a soluble protein in different physiological and pathological fluids. In addition, it contains a high density of repetitive sequences, including Alu, MER, and MIR elements, which are not present at equivalent positions in class I MHC genes. Finally, its 5'-flanking region lacks the class I MHC regulatory complex and the interferon consensus sequence characteristic of class I MHC genes. These findings may explain the different expression pattern of Zn-alpha 2-gp and class I MHC genes in human tissues. Southern blot hybridization of DNA from several species with a cDNA probe indicated that Zn-alpha 2-gp genes are present in a wide variety of animal species, including monkey, rat, mouse, dog, cow, and rabbit. The human genome also contains a putative Zn-alpha 2-gp pseudogene that has been isolated and partially characterized. This pseudogene has an intron-exon organization identical to that of the functional gene, but it presents two deleterious mutations in the third exon that lead to the appearance of premature stop codons. Finally, considering the lack of polymorphism in the Zn-alpha 2-gp gene in comparison with MHC genes, putative roles for this human glycoprotein in the transport of nonpolymorphic substances or in intercellular recognition processes are proposed.

Amino Acid Sequence↗

PubMed1997

Congenital adrenal hyperplasia.

Cogenital adrenal hyperplasia (CAH) is a family of genetic disorders from a deleterious mutation in a gene encoding adrenal steroidogenic enzyme essential for cortisol biosynthesis. Recent molecular advances have provided the genetic basis for the phenotypic variability in CAH, a means for accurately genotyping family members of CAH patients including prenatal prediction of the genotype in fetuses at risk of the disorder, and have helped to better define the hormonal criteria for the varying spectrum of CAH disorders. Biochemical advances have simultaneously aided the diagnosis and therapeutic monitoring of CAH patients. Prenatal maternal dexamethasone therapy for fetal CAH prevents or minimizes virilizing sequelae in the majority of prenatally treated affected females, but was associated with significant maternal side effects. Newborn screening for CAH has contributed to the prevention of morbidity of delayed diagnosis of CAH in more than two third of affected neonates. Current treatment methods, however, may not be optimal for achieving normal genetic height and appropriate weight in CAH patients, and more effective approaches to CAH therapy remain to be explored.

Adrenal Hyperplasia, Congenital↗

PubMed1997

Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human.

Krebs cycle disorders constitute a group of rare human diseases which present an amazing complexity considering our current knowledge on the Krebs cycle function and biogenesis. Acting as a turntable of cell metabolism, it is ubiquitously distributed in the organism and its enzyme components encoded by supposedly typical house-keeping genes. However, the investigation of patients presenting specific defects of Krebs cycle enzymes, resulting from deleterious mutations of the considered genes, leads to reconsider this simple envision by revealing organ-specific impairments, mostly affecting neuromuscular system. This often leaves aside organs the metabolism of which strongly depends on mitochondrial energy metabolism as well, such as heart, kidney or liver. Additionally, in some patients, a complex pattern of tissue-specific enzyme defect was also observed. The lack of functional additional copies of Krebs cycle genes suggests that the complex expression pattern should be ascribed to tissue-specific regulations of transcriptional and/or translational activities, together with a variable cell adaptability to Krebs cycle functional defects.

Adolescent↗

PubMed1988

Molecular genetics of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia results from a deficiency in any of the five enzymes necessary to synthesize cortisol from cholesterol: cholesterol desmolase (P450scc), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (P450c17), 21-hydroxylase (P450c21) and 11-hydroxylase (P450c11). P450scc and P450c11 are structurally-related mitochondrial cytochrome P450 enzymes, whereas P450c17 and P450c21 are microsomal enzymes. The P450scc gene, CYP11A, is located on chromosome 15, and the P450c17 gene, CYP17, is on chromosome 10. The P450c21 gene, CYP21B, and a pseudogene, CYP21A, are located in the HLA major histocompatibility complex on chromosome 6p, while the P450c11 gene, CYP11B, is on chromosome 8q along with a second related gene of unknown function. Thus, despite common regulation by ACTH, there is no clustering of the genes for steroidogenic enzymes. CYP11A and CYP11B have an identical intron-exon organization, and CYP17 and CYP21B have similar gene structures, but the two pairs of genes encoding mitochondrial and microsomal P450 enzymes resemble each other poorly. More than 90% of cases of congenital adrenal hyperplasia result from 21-hydroxylase deficiency, and most of the remainder are caused by 11-hydroxylase deficiency. About one-quarter of 21-hydroxylase deficiency alleles are associated with a deletion of all or part of CYP21B. Most of the remaining mutant alleles result from transfers of deleterious mutations from the CYP21A pseudogene to CYP21B, a process termed gene conversion. These mechanisms provide an explanation for the relatively high frequency of 21-hydroxylase deficiency. The clinical severity of various forms of 21-hydroxylase deficiency may be roughly correlated with particular mutations.

Adrenal Cortex Hormones↗

PubMed1997

Insights into the evolutionary process from patterns of DNA sequence variability.

Studies of DNA sequence diversity, particularly in Drosophila, reveal both the complexity of natural selection and the importance of the interaction of natural selection and variation in rates of recombination within genomes and between species in determining levels of sequence variability in different genes and different species. The impact of both adaptive and deleterious mutations are evident. Extension of these types of studies to other organisms has begun in earnest.

Adaptation, Biological↗

PubMed2000

Incidence of BRCA1/2 germ line alterations in a high risk cohort participating in a phase II chemoprevention trial.

It is unknown what proportion of women at high risk for breast cancer, entering phase II chemoprevention trials, have BRCA1/2 alterations, and whether their initial biomarker patterns or response to preventive interventions will differ between carriers and non-carriers. As part of a 6-month phase II chemoprevention trial of diflouromethlyornithine (DFMO), high-risk subjects (family history, prior precancerous breast disease or prior breast cancer), who had random peri-areolar fine needle evidence of epithelial hyperplasia with or without atypia, were offered genetic counselling and testing at the completion of their study participation. 97% of the 119 women eligible for testing underwent BRCA1/2 gene sequencing, 3 declined. 26 (22%) of the 116 women had an alteration in BRCA1/2. Known deleterious mutations were present in 3 (3%), uncertain significance mutations in 19 (16%), and probable polymorphisms in 6 (5%). There does not appear to be a difference in initial biomarker distribution between participants with and without germ line alterations.

Adult↗

PubMed2001

Activation of JNK1 contributes to dystrophic muscle pathogenesis.

Duchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product. Subsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood. Dystrophin provides a structural base for the assembly of an integral membrane protein complex. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage. However, the development of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models. Although activation of a detrimental signal transduction pathway has been suggested as a probable cause, a specific cellular cascade has yet to be defined. Here, it is shown that murine models of DMD displayed a muscle-specific activation of JNK1. Independent activation of JNK1 resulted in defects in myotube viability and integrity in vitro, similar to a dystrophic phenotype. In addition, direct muscle injection of an adenoviral construct containing the JNK1 inhibitory protein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated signal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis.

Adenoviridae↗

PubMed2004

Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae.

The ability to develop adequate immunity to intracellular bacterial pathogens is unequally distributed among human beings. In the case of tuberculosis, for example, infection with Mycobacterium tuberculosis results in disease in 5-10% of exposed individuals, whereas the remainder control infection effectively. Similar interindividual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis, and other chronic infectious diseases, including viral infections. The outcome of infection is influenced by many factors, such as nutritional status, co-infections, exposure to environmental microbes, and previous vaccinations. It is clear, however, that genetic host factors also play an important part in controlling disease susceptibility to intracellular pathogens. Recently, patients with severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis BCG) or Salmonella spp have been identified. Many of these patients were unable to produce or respond to interferon gamma, due to deleterious mutations in genes that encode major proteins in the type 1 cytokine (interleukin 12/interleukin 23/interferon gamma) axis (interleukin 12p40/interleukin 23p40, IL12 receptor beta1/IL23 receptor beta1, interferon gamma receptors 1 and 2, or signal transducer and activator of transcription 1). This axis is a major immunoregulatory system that bridges innate and adaptive immunity. Unusual mycobacterial infections were also reported in several patients with genetic defects in inhibitor of NFkappaB kinase gamma, a key regulatory molecule in the nuclear factor kappaB pathway. New findings discussed in this review provide further and sometimes surprising insights into the role of type 1 cytokines, and into the unexpected heterogeneity seen in these syndromes.

Cytokines↗