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PubMed2002

Inherited neuropathies.

Inherited neuropathies are common and are usually caused by mutations in genes that are expressed by myelinating Schwann cells or neurons, which is the biological basis for long-standing distinction between primary demyelinating and axonal neuropathies. Neuropathies can be isolated, the primary manifestation of a more complex syndrome, or overshadowed by other aspects of the inherited disease. Increasing knowledge of the molecular-genetic causes of inherited neuropathies facilitates faster, more accurate diagnosis, and sets the stage for development of specific therapeutic interventions.

DNA Mutational Analysis↗
PubMed1993

Inherited enzyme deficiencies in livestock.

The biochemical basis of over 300 inherited diseases has been defined in humans, and the majority involve abnormalities in enzymes. The rate of discovery of new defects is accelerating as biochemical and molecular technologies improve. The majority of inherited defects are expressed before puberty and approximately 25% are apparent at birth. Genomes of other mammals are similar and have been subjected to similar mutation pressures; therefore, it is probable that a range of inherited defects exists in livestock similar to that in humans. Because modern livestock populations have emerged from small population bases, the range of genetic aberrations, within breeds, will be less than in the general human population. Even if there is a 10-fold difference, however, there will be a bewildering array of defects possible in each breed. Because the level of inbreeding within livestock populations is greater than in the general human population, on the other hand, the prevalence of specific defects will be higher. It is probable that a high prevalence of a lethal recessive defect could occur within a particular livestock population and escape recognition. First, livestock producers accept a relatively high neonatal mortality rate without seeking a diagnosis. Second, few if any veterinary diagnostic facilities possess either the instrumentation or the analytic skills essential for investigating the vast range of potential inborn errors of metabolism. Third, national selection programs--e.g., those employed within the dairy industry--tend to use production data from adult progeny in selection. Consequently, the programs would not detect differences in fetal or neonatal mortality rates among descendants of specific sires until a deleterious defect had been widely disseminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Mendelism and medicine: controlling human inheritance in local contexts, 1920-1960.

The rise of Mendelism has often been associated with the development of agricultural sciences and the attempts to improve varieties and select new plants. In contrast, historians have tended to stress the tensions between Mendelism and medicine originating in the influence of eugenicists. The use of Mendel's laws in the context of discussing human inheritance and the transmission of pathologies was nonetheless pervading the medical literature from the 1920s onwards. This paper investigates the dynamics of medical Mendelism by comparing developments in France and in Britain. In contrast to reluctant botanists and zoologists, the elite of the French medical profession was often 'Mendelian'. Mendel's laws have accordingly been integrated into a complex approach to the familial transmission of pathologies, into a theory of pathological inheritance, which combined genetics, germ theory and hygiene. This approach was widely accepted among the paediatricians and obstetricians active in both the eugenics movement and the natalist movement. The career of the pediatrician R. Turpin is a good example of the visibility of this form of medical Mendelism and of its long-lasting impact on genetic research in the country. In Britain, where the social basis of eugenics was not the medical profession, eugenics' claims often clashed with public health and hygiene priorities. Medical Mendelism was in the first place supported and advanced by doctors and scientists participating in the public debates about the care of 'feeble minded' and the classification of social groups. As revealed by the trajectory of L. Penrose this context favoured the linkage between statistics and pedigree analysis, thus leading to the 'Mendelization' of human pathologies. After the war, this Mendelization in turn facilitated the rise of medical genetics as a speciality focusing on genetic counselling and on the management of computable hereditary risks. This comparative analysis thus highlights: a) the influence of local medical cultures on the fate of Mendelism; b) the continuities between the pre-war studies of pathological inheritance and the post-war rise of medical genetics.

Animals↗
PubMed1999

Using transgenic models to study the pathogenesis of keratin-based inherited skin diseases.

In the past decade, the production of transgenic animals whose genome is modified to contain DNA transgenes of interest has significantly contributed to expand our understanding of the molecular etiology and pathobiology of several inherited skin diseases. This technology has led to the discovery that mutations affecting specific keratin genes are responsible for a wide spectrum of inherited bullous diseases, which are collectively characterized by blistering after minor trauma. Type I and type II keratin proteins are restricted to, and very abundant in, epithelial cells, where they occur as a pancytoplasmic network of cytoskeletal filaments. Although it had long been suspected that a primary function of keratin filaments may be to contribute to the physical strength of epithelial sheets, a formal demonstration came from studies of transgenic mouse models and patients suffering from keratin-based blistering diseases. Here we review the basic characteristics of keratin gene and their proteins and relate them to the molecular pathogenesis of relevant inherited skin blistering diseases. A particular emphasis is placed on the role of transgenic mouse models in the past, current, and future studies of these genodermatoses.

Animals↗
PubMed2000

Progress in genetic counselling and prenatal diagnosis of maternally inherited mtDNA diseases.

Mitochondrial DNA is almost entirely maternally inherited. Thousands of copies of mitochondrial DNA are present in every nucleated cell and in most normal individuals these are virtually identical (homoplasmy). Mitochondrial DNA diseases may be caused by mutations in either mitochondrial (Nature 1988;331:717-719) or nuclear genes (Nature 1989;339(6222):309-311; Br J Hosp Med 1996;55:712-716) and hence give rise to maternal or autosomal patterns of inheritance. Antenatal diagnosis of mitochondrial diseases based on chorionic villus sampling is available for Mendelian disorders and the syndromes caused by mutations at bp 8993 (associated with both Leigh's syndrome or neurogenic weakness ataxia and retinitis pigmentosa). However, prenatal diagnosis of many other maternally inherited mitochondrial DNA diseases is less reliable because it is not possible to predict the way in which heteroplasmic mitochondrial DNA mutations segregate within tissues with confidence. This review focuses on the substantial progress that has been made recently, and on the applicability of prenatal diagnosis to genetic counselling in this field.

DNA, Mitochondrial↗
PubMed1997

Epigenetic inheritance in the mouse.

Acquired epigenetic modifications, such as DNA methylation or stable chromatin structures, are not normally thought to be inherited through the germline to future generations in mammals [1] [2]. Studies in the mouse have shown that specific manipulations of early embryos, such as nuclear transplantation, can result in altered patterns of gene expression and induce phenotypic alterations at later stages of development [3] [4] [5]. These effects are consistent with acquired epigenetic modifications that are somatically heritable, such as DNA methylation. Repression and DNA methylation of genes encoding major urinary proteins, repression of the gene encoding olfactory marker protein, and reduced body weight can be experimentally induced by nuclear transplantation in early embryos [4]. Strikingly, we now report that these acquired phenotypes are transmitted to most of the offspring of manipulated parent mice. This is the first demonstration of epigenetic inheritance of specific alterations of gene expression through the germline. These observations establish a mammalian model for transgenerational effects that are important for humal health, and also raise the question of the evolutionary importance of epigenetic inheritance.

Amino Acid Sequence↗
PubMed2004

Inherited bleeding disorders: disorders of platelet adhesion and aggregation.

Platelet aggregation at sites of vascular injury is essential for the formation of the primary haemostatic plug. The mechanism of platelet aggregation under conditions of physiological flow is a complex multistep process, which requires the synergistic action of several different platelet receptors. Platelet interaction with collagen at sites of damage to the vascular endothelium involves adhesion, activation, secretion of platelet granular contents and finally aggregation. Other agonists other than collagen, such as fibrinogen, vWF and soluble agonists released from activated platelets (thromboxane A2 (TXA2) and ADP) are involved in platelet aggregation. Platelets express a variety of receptors including GP Ib-IX-V, GP VI, GP Ia-IIa and GP IIb-IIIa. One aspect of this complexity of function is the variety of inherited defects of platelet function. Hereditary disorders of platelet adhesion are Bernard-Soulier syndrome and von Willebrand disease. Glanzmann thrombasthenia is an inherited disorder of platelet aggregation. The application of molecular biology to the study of platelet disorders has identified defects in other collagen receptors, ADP receptors and TXA2 receptors. Defects affecting TXA2 production, the generation of procoagulant activity and secretion from dense bodies and alpha-granules are also encountered. Other rare diseases, Chediak-Higashi, Hermansky-Pudlak and Wiskott-Aldrich syndrome also affect platelet storage granules. In this article, recent advances in the understanding of platelet function and knowledge of inherited disorders that affect platelet adhesion and aggregation is reviewed. As progress advances towards individualisation of therapy the phenotypic bleeding tendency of each patient becomes relevant.

Blood Coagulation Disorders↗
PubMed2002

Isogamous, hermaphroditic inheritance of mitochondrion-encoded resistance to Qo inhibitor fungicides in Blumeria graminis f. sp. tritici.

A mutation of glycine to alanine at position 143 in the mitochondrial cytochrome b amino acid sequence of Blumeria graminis f. sp. tritici cosegregated with the QoI-resistant phenotype in a ratio of 1:1 in a cross between a sensitive and a resistant isolate. This mutation was used as a mitochondrial marker to determine whether mitochondrial inheritance in B. graminis was anisogamous, as in heterothallic Neurospora sp., or isogamous and hermaphroditic, as in Aspergillus nidulans. Segregation of mitochondrial genotypes in B. graminis f. sp. tritici was consistent with inheritance of mitochondria being hermaphroditic and isogamous, in that all ascospores from an individual cleistothecium had the same mitochondrial genotype and that either parent could act as the maternal parent of a cleistothecium. Within each cleistothecium, nuclear segregation occurred independently of mitochondrial inheritance, as shown by segregation of resistance to the fungicide triadimenol and by segregation of avirulences to the wheat cultivars Galahad (Pm2), Armada (Pm4b), and Holger (Pm6).

Amino Acid Sequence↗
PubMed2001

Inheritance of osteosarcoma and Paget's disease of bone: a familial loss of heterozygosity study.

Pagetoid osteosarcoma is a complication of Paget's disease of bone. Sarcomatous transformation is most often seen in severe, long-standing Paget's disease. Familial clustering of Paget's disease has been described with apparent autosomal dominant inheritance with high penetrance by the sixth decade. Although definitive proof of the specific gene involved remains elusive, some researchers have shown loss of heterozygosity in a region of chromosome 18q in a relatively high percentage of studied patients affected with either Paget's disease alone, in Pagetoid osteosarcoma, and in uncomplicated osteosarcoma. Our patient was diagnosed with Pagetoid osteosarcoma and had a first-degree relative with history of the same. We hypothesized that our patient's tumor samples might contain a similar genetic abnormality. Our analysis of several polymorphic markers from the chromosome 18q21-22 region showed loss of maternally inherited alleles throughout the region. This finding is similar to those described previously and provides further evidence of a susceptibility region relating to this disease. This report describes a father and son, their young ages at diagnosis of Pagetoid sarcoma, the identical sites of disease involvement, and a loss of heterozygosity study illustrating the inheritance of the presumed defective gene.

Adult↗
PubMed2000

Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q.

Paget's disease of bone is a common disorder characterized by focal abnormalities of bone turnover which are associated with bone pain bone deformity and an increased risk of pathological fracture. Genetic factors play an important role in the pathogenesis of Paget's disease, and recent genetic linkage studies have shown that in some families the disease is linked to a candidate locus on chromosome 18q21-22, which also harbors the gene for the related inherited condition, familial expansile osteolysis. In this study we characterized the patterns of inheritance in a series of 269 individuals from a further 50 kindreds with familial Paget's disease and sought to determine how frequently the disease was linked to chromosome 18q. Segregation analysis showed that 54% of individuals had developed Paget's disease by the age of 55, with an equal distribution in men in women, consistent with an autosomal dominant mode of inheritance with high penetrance. In families where parental data were available, there was no difference in the frequency of disease transmission between paternal or maternal sources. Linkage studies with nine polymorphic markers spread across the candidate region did not support linkage to 18q under models of homogeneity or heterogeneity. Indeed, the summated multipoint lodscores were consistently below -2.0 across the region, providing strong evidence against linkage. These studies confirm the presence of genetic heterogeneity in familial Paget's disease but show that linkage of the disease to the previously identified candidate locus on chromosome 18q21-22 is relatively uncommon.

Chromosomes, Human, Pair 18↗
PubMed1989

Non-additive inheritance of glucose phosphate isomerase activity in mice heterozygous at the Gpi-1s structural locus.

The activity of blood glucose phosphate isomerase (GPI-1) in mice heterozygous for various alleles at the Gpi-1s structural locus (heterozygotes a/b, a/c and b/c) was significantly higher than expected, on the basis of additive inheritance, from the levels in parental homozygotes. Moreover, the GPI-1 activity was higher in a/b heterozygotes than in either parent (heterosis). Studies of heat stability with kidney homogenates revealed that the relative stabilities of GPI-1 dimers was AA greater than AB greater than BB greater than AC greater than or equal to BC greater than CC. Differences in dimer stabilities in vivo would affect the total GPI-1 levels in heterozygotes and could account for non-additive inheritance but would be insufficient to explain heterosis for GPI-1 activity. Other possible contributing factors include unequal production or stability of monomers, or higher catalytic activity of heterodimers. Monomers could also associate non-randomly but this would not be sufficient to explain heterosis. It is clear that non-additive inheritance patterns may be produced by variants of either structural or regulatory genes.

Animals↗
PubMedDate not supplied

Inheritance of T-associated sex reversal in mice.

We previously identified a primary sex-determining locus, Tas, on mouse Chr 17 that causes ovarian tissue development in C57BL/6J Thp/+ and TOrl/+ individuals if the AKR/JY chromosome is present. We hypothesized that Tas is located within the region of Chr 17 deleted by Thp and TOrl and that C57BL/6J carries a diagnostic Tas allele, based on the observation that ovarian tissue develops in XY mice when Thp is on a C57BL/6J inbred strain background, whereas normal testicular development occurs when Thp is on a C3H/HeSnJ inbred strain background. To test this hypothesis, we mated (C57BL/6J x C3H/HeSnJ)F1 females to C57BL/6J Thp/+ hermaphrodites. As expected, half of the XY Thp/+ offspring developed ovarian and testicular tissue while half developed exclusively testicular tissue. Unexpectedly, the inheritance of selected Chr 17 molecular loci was independent of gonadal development, as half of the male and hermaphroditic offspring inherited C3H/HeSnJ-derived Chr 17 loci and half inherited C57BL/6J-derived Chr 17 loci. We conclude that for ovarian tissue to develop in an XY Thp/+ or XY TOrl/+ individual (1) Tas must be present in a hemizygous state, which is accomplished by heterozygosity for the Thp or TOrl deletions; (2) the AKR/J-derived Y chromosome must be present; and (3) an additional locus involved in primary sex determination must be present in a homozygous C57BL/6J state. This newly identified gene may be one of the previously defined loci, tda-1 or tda-2.

Animals↗
PubMed1979

The inheritance of thiabendazole resistance in Haemonchus contortus.

Haemonchus contortus worm populations isolated from naturally infected sheep at the Pastoral Research Laboratory, Armidale, N.S.W., were found to contain approximately 20% of worms resistant to a 50 mg/kg dose of thiabendazole. Following 3 generations of selection with 50 mg/kg thiabendazole the number of worms removed by the anthelmintic was too small to detect differences between treated and control groups. After more than 15 generations of selection, matings between males from the selected strain and non-resistant females produced resistant males and females in equal numbers. Thus, thiabendazole resistance does not appear to be sex-linked. A dose--response assay on the F2 adults indicated that worms from female resistant x male non-resistant crosses were more resistant than F2 adults of the reciprocal cross. An in vitro technique that identified thiabendazole-resistant eggs by their ability to hatch in a solution containing thiabendazole and 0.1% NaCl solution was also used to study the inheritance of resistance. F1 eggs had similar LC50's to the resistant parents. F2 and back-cross eggs from an original mating of thiabendazole-resistant females x non-resistant males had a higher LC50 than F2 and back-cross eggs from the reciprocal mating, indicating a degree of matroclinous inheritance of resistance. However, the resistant parents had tolerances to thiabendazole exceeding those of F2. F3 eggs had a resistance distribution that ranged from that of the resistant to the non-resistant parent. No significant deviation from linearity was observed in any of the dose--response lines. These results indicate that thiabendazole resistance in H. contortus worms is inherited as an autosomal and semi-dominant trait.

Animals↗
PubMed2001

Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy.

Inherited defects in myocardial long-chain fatty acid metabolism are increasingly recognized as a cause of cardiomyopathy and sudden death in children. To evaluate whether the phenotypic expression of these genetic diseases could be delineated using positron emission tomography (PET), 11 patients with inherited defects in fatty acid metabolism were evaluated and results were compared with those of 6 nonaffected siblings. Myocardial perfusion, myocardial oxygen consumption (MVO2), and long-chain fatty acid metabolism were determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO2 or plasma substrate levels between groups. Patients with defects in enzymes of fatty acid beta-oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase deficiencies) (n = 5) had diminished myocardial palmitate oxidation compared with healthy siblings (3.2 +/- 3.0 vs. 13.0 +/- 5.6 nmol/g per min, p < 0.03) and a decrease in the percentage of MVO2 accounted for by palmitate (2% +/- 3% vs. 9% +/- 5%, p < 0.04). In these patients, extracted palmitate was shunted into a slow-turnover compartment (predominantly reflecting esterification to triglycerides) with expansion of palmitate in that pool (185 +/- 246 compared with 27 +/- 67 nmol/g in healthy siblings,p < 0.02). In contrast, myocardium of patients with carnitine deficiency (n = 6) (all on oral carnitine therapy) had normal palmitate extraction but expansion of the interstitial/cytosolic fatty acid pool (617 +/- 399 vs. 261 +/- 73 nmol/g in healthy siblings, p < 0.04), suggesting different mechanisms for handling upstream fatty acyl intermediates. Thus, PET can be used to noninvasively assess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affected patients.

Acetates↗
PubMed2003

Personal theories of inheritance, coping strategies, risk perception and engagement in hereditary non-polyposis colon cancer families offered genetic testing.

From the geneticist's (or 'genetic counsellor's') perspective, lay models of inheritance can be perceived as problematic because they might interfere with understanding and acceptance of the explanation of inheritance provided in genetic counselling. The work presented here forms part of a larger qualitative grounded-theory study where the aim was to develop theory that could explain variations in adjustment to genetic testing for hereditary non-polyposis colon cancer (HNPCC). Ten of the 29 individuals interviewed who were at 50% or 25% risk used a 'personal theory of inheritance' to justify or explain a belief that they did, or did not, carry the family mutation. Two others indicated that, as a coping strategy, they chose to believe themselves to be carriers. This article presents part of the theory of engagement that was constructed using this data, relating to the process of development of risk perception. The theory suggests that for some individuals, these beliefs can form part of a process of coping and coming to terms with risk. An exploration of these processes may help practitioners to better understand the complexity of risk perception in individuals at genetic risk for cancer, particularly those preparing for predictive test results. Further development and testing of the theory is discussed.

Adaptation, Psychological↗
PubMed1989

Inheritance of spatial learning ability in inbred mice: a classical genetic analysis.

The inheritance of spatial learning ability in inbred mice was examined by performance of a classical genetic cross between the 2 inbred strains C57BL/6Ibg and DBA/2Ibg. The inbreds were crossed to produce the 1st filial generation (F1) hybrids. F1 mice were bred to each other and were backcrossed to the parental strains to produce 3 hybrid generations with recombinant genotypes. The animals were tested for spatial learning ability in the Morris water task. All hybrid generations showed greater spatial learning ability than the inbreds, with F1 hybrids showing the greatest degree of spatial learning. The inheritance pattern for spatial learning differed between male and female mice, with males showing a type of inheritance in which dominant genes made the major contribution to the expression of the behavior. Females showed equal contributions of dominance deviation and additive genetic effects. The results are discussed in terms of fitness value to the animals.

Animals↗
PubMed1999

Oligopeptide-repeat expansions modulate 'protein-only' inheritance in yeast.

The yeast [PSI+] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a 'protein only' mechanism reminiscent of the 'protein-only' transmission of mammalian prion diseases. The underlying molecular mechanisms for both are poorly understood and it is not clear how similar they might be. Sup35, the [PSI+] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats-PQGGYQQYN in Sup35 and PHGGGWGQ in PrP. Repeat expansions in PrP produce spontaneous prion diseases. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI+] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in beta-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.

Fungal Proteins↗
PubMed1998

Expression and inheritance of multiple transgenes in rice plants.

The ability to control integration, inheritance, and expression of multiple transgenes is a prerequisite for manipulating biosynthetic pathways and complex agronomic characteristics in plants. One hundred and twenty-five independent transgenic rice plants were regenerated after cobombarding embryogenic tissues with a mixture of 14 different pUC-based plasmids. Eighty-five percent of the R0 plants contained more than two, and 17% more than nine, of the target genes. Plants containing multiple transgenes displayed normal morphologies and 63% set viable seed. Multigene cotransformation efficiency was correlated with the ratio in which the plasmids were mixed with respect to the selectable marker. All target genes had an equal chance of integration, indicating that the nature of the coding region had no effect on the efficiency of integration. Three plant lines containing 11, 10, and 9 transgenes, respectively, were analyzed for patterns of integration and inheritance until the R3 generation. Integration of multiple transgenes occurred at either one or two genetic loci, with inheritance conforming to a 3:1 Mendelian ratio. Coexpression of four marker genes was investigated until the R2 generation.

Acetyltransferases↗