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Parental age and birth order were studied in 251 patients with cerebral palsy. No parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia. These observations indicate that some cases of athetoid/dystonic or hemiplegic cerebral palsy might arise by fresh dominant genetic mutation.
Scapuloperoneal spinal muscular atrophy (SPSMA) is a neuromuscular disorder characterized by weakness in the distribution of shoulder girdle and peroneal muscles. We have previously described a large New England kindred with autosomal dominant SPSMA and have subsequently linked this family trait to 12q24.1-q24.31. In this family, disease expression becomes more severe and progressive in successive generations, suggesting genetic anticipation. Accordingly, we have investigated the thirteen known CAG/CTG repeat loci on chromosome 12 that could be tested by using the polymerase chain reaction as candidate genetic mutations in SPSMA. None of these loci is expanded.
Biomedical microelectromechanical systems (BioMEMS) are rapidly emerging in many areas of genetic analysis. These devices demonstrate potential for rapid analysis using modular components capable of sample purification, amplification, mutation discrimination and detection on small, portable point-of-care instruments. Here, various approaches to genetic mutation detection and the modern analysis platform, capillary electrophoresis, will be briefly reviewed. Microfluidic devices will be discussed in relation to fabrication techniques, mutation detection using simple electrophoretic separations, multiplexed designs and modular functionalities, as well as challenges and issues surrounding this technology.
Severe acute respiratory syndrome (SARS) caused by SARS-associated coronavirus (SARS-CoV) is a fatal disease. Prevention of future outbreaks is essential and requires understanding pathogenesis and evolution of the virus. We have isolated a SARS-CoV in China and analyzed 47 SARS-CoV genomes with the aims to reveal the evolution trends of the virus and provide insights into understanding pathogenesis and SARS epidemic. Specimen from a SARS patient was inoculated into cell culture. The presence of SARS-CoV was determined by RT-PCR and confirmed by electron microscopy. Virus was isolated followed by the determination of its genome sequences, which were then analyzed by comparing with other 46 SARS-CoV genomes. Genetic mutations with potential implications to pathogenesis and the epidemic were characterized. This viral genome consists of 29,728 nucleotides with overall organization in agreement with that of published isolates. A total of 348 positions were mutated on 47 viral genomes. Among them 22 had mutations in more than three genomes. Hot spots of nucleotide variations and unique trends of mutations were identified on the viral genomes. Mutation rates were different from gene to gene and were correlated well with periodical or geographic characteristics of the epidemic.
Vitamin D is deeply involved in a wide variety of biological events such as calcium homeostasis, bone formation and cellular differentiation. An active form of vitamin D, 1alpha,25(OH)2D3, serves as a vitamin D receptor (VDR)-specific ligand to activate the expression of a particular set of target genes. 1Alpha,25(OH)2D3, is biosynthesized from cholesterol, and at the final biosynthesis step, 25-hydroxyvitamin D3 1alpha-hydroxylase [1alpha(OH)ase] in kidney conducts 1alpha-hydroxylation of 25(OH)2D3. This enzymatic activity is under multihormonal regulation and critical for the biosynthesis. Molecular cloning of 1alpha(OH)ase from several species has revealed that this enzyme belongs to a member of the cytochrome P450 enzyme superfamily, with highest homologies to the P450 hydroxylases for vitamin D derivatives. The renal gene expression is strictly regulated at the transcriptional level through its gene promoter by PTH and calcitonine (positive) and 1alpha,25(OH)2D3 (negative). Most importantly in clinical aspects, genetic mutations in this gene to abolish the enzymatic activity are now shown to cause the one of three kinds of hereditary rickets, vitamin D-dependent rickets type I.
Identification of mutations responsible for human monogenic hereditary diseases has lately undergone rapid development. It is now possible to establish the mutation spectrum for a given genetic disease and international databases are now available on the Internet. New mutational mechanisms have been identified:transposition, inversion, trinucleotide repeat expansion. At the disease level, knowledge of molecular defects has allowed to better delimit mechanisms of gain or loss of function, to understand dominant or recessive mode of inheritance, to explain anticipation phenomena, to identify founder effect amid a selected population, to establish, in some privileged cases, phenotype-genotype correlations and above all to elicit allelic and genetic heterogeneity hitherto unsuspected. Identification of deleterious mutations is also the basis of diagnosis at the gene level which today has a growing impact on genetic counselling and prenatal diagnosis.
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We studied the prevalence of genetic thrombophilic mutations in patients on chronic oral anticoagulant treatment (OAT) who had bleeding complications. In a case-control study we found ten (12.8%) carriers of factor V Leiden and two (2.5%) carriers of the PT20210A mutation among 78 patients with a history of moderate-severe bleeding while on OAT, and seven (4.4%) and four (2.5%), respectively, among 156 matched patients with no bleeding while on OAT (odds ratio 3.1+/-1.6, p=0.026). In patients on chronic OAT, FV Leiden is a risk factor for moderate-severe bleeding.
Genetic variation inferred from large-scale amino acid composition comparisons among genomes and chromosomes of several species, Saccharomyces cerevisiae, Drosophila melanogaster, Ceanorhabditis elegans, H. sapiens, is shown to be correlated (highest, r(2)=0.9855, p<0.01) with reported mutation rates for various genes in these species. This study, based largely on pseudogene data, helps to establish reference mutation frequencies that are likely to be representative of overall genome mutation rates in each of the species examined, and provides further insight into heterogeneity of mutation rates among genomes.
The results of recent molecular biological studies of aging and longevity confirmed substantial genetic contribution to the life span. The analysis of these findings showed substantial role of specific mutations in genes involved in regulatory processes on both the extra- and intracellular levels. We suggest that difference in responses of intact and mutant animals to the same set of environmental signals may be useful to clarify contribution of organism-environment interactions into the rate of aging, mortality and longevity of respective organisms. In our opinion such clarification is important for better understanding the origin of natural senescence and its dependence on external conditions.
Knowledge concerning the genetic defects underlying malignant hyperthermia (MH) has expanded rapidly in recent years. In contrast, our understanding of the accompanying physiological changes is less clear. In this regard, the aim of this study was to determine whether normal swine and swine susceptible to MH (both heterozygous and homozygous animals) differ in their abilities to incorporate n-3 (omega 3) fatty acids into their skeletal and heart muscles. Swine of each genotype were fed either a diet rich in n-3 fatty acids (i.e., 5% fish oil) or an equal caloric diet low in n-3 fatty acids (i.e., 5% coconut oil). All dietary supplementations were given over a 13-week period. Subsequently, for each muscle type the following was determined: 1) the relative fatty acid profiles of eight different phospholipid classes and of neutral lipids, and 2) the total phospholipid and the total lipid content. The incorporation of n-3 fatty acids (i.e., eicosapentaenoic acid and docosahexaenoic acid) occurred within the various phospholipids and neutral lipids without influencing their total lipid content. The increased content of n-3 fatty acids in neutral lipids of skeletal muscle was related to a decreased content of medium-chain saturated fatty acids, whereas an increased incorporation of n-3 fatty acids into the membrane phospholipids was often related to a decreased content of linoleic acid and/or arachidonic acid. In general, the pattern of n-3 fatty acid incorporation was considerably different between the normal animals and the MH homozygous and heterozygous animals. The significant interaction between diet-induced n-3 fatty acid profiles and the stress-susceptible MH genotype may indicate an altered mechanism for fatty acid turnover and a repair mechanism to maintain cellular functions and structure.
Medullary thyroid cancer (C.M.T.) can be a sporadic form generally in adults or a heredofamilial form where the first symptom appears in pediatric and adolescent age. The hereditary form can be isolated or associated with others endocrine neoplasias of type 2: MEN2a (with or without cutaneous lichen amyloidosis) and MEN2b. The responsible gene of the transmission has been identified in proto-oncogene RET localized on chromosome 10. Point form mutations of this proto-oncogene have been found on exons 10 and 11 in MEN2a and on 16 in MEN2b. In our study on 64 subjects, who belong 11 familiar groups, affected by MEN2a, MEN2b and familiar C.M.T., underwent a genetic research to look for point form mutations of proto-oncogene RET with PCR followed by the analysis of restriction. A genetic mutation has been revealed in 25 subjects: 18 were already known affected by MEN2 and so surgical treated and 7 seemed healthy (mean age 17.4 years, range 10-25). These 7 patients has been undergone clinical research and surgical treatment: a total thyroidectomy associated a lymphectomy of the central compartment. In all cases the histological exam showed C.M.T. moreover a patient had metastasis in lymph nodes of the central compartment. Another had hyperparathyroidism and pheochromocytoma treated with total thyroidectomy, parathyroidectomy and bilateral laparoscopic adrenalectomy. The identification in a very early age of carrier subjects of hill's gene inside an affected family, permits the execution of a prophylactic total thyroidectomy to prevent the C.M.T.. The penetrance of this neoplasia in hereditary form is 100%.
Epidermolytic hyperkeratosis (EH) is a skin disease caused by mutations in the genes encoding K1 and K10, the differentiation-specific keratins of epidermis. To explore the heterogeneity of mutations and to assess whether a correlation exists between disease severity and the extent to which a mutation interferes with keratin network formation, we determined the genetic bases of four severe incidences of EH and one unusually mild case. Two severe cases have the same mutation, K10-R156:C, at a conserved arginine that we previously showed was mutated to a histidine in two unrelated EH families. An additional severe case has a mutation six residues away, still within the amino end of the alpha-helical rod domain of K10. The other severe case has a mutation in the conserved carboxy end of the K1 rod. In contrast, affected members of the atypically mild family have a mutation just proximal to the conserved carboxy end of the K10 rod. By genetic engineering and gene transfection, we demonstrate that each mutation is functionally responsible for the keratin filament aberrations that are typical of keratinocytes cultured from these patients. Moreover, we show that the mild EH mutation less severely affects filament network formation. Taken together, our studies strengthen the link between filament perturbations, cell fragility, and degeneration.
Resistance of coagulation factor Va to inactivation by activated protein C (APCR) is associated with a point mutation in which adenine is substituted for guanine at nucleotide 1691 in the gene coding for factor V (FV Leiden). To date, this mutation of factor V is the most frequent genetic risk factor for venous thrombophilia. In this report, we describe the adaptation of an automatable oligonucleotide ligation assay (OLA) to detect the mutation in polymerase chain reaction-amplified DNA samples from 40 normal, 20 affected heterozygous, and 3 affected homozygous individuals. The genotypes determined by conventional allele-specific restriction enzyme site analysis were in complete concordance with the results obtained by ELISA-based oligonucleotide-ligation assay. The automated oligonucleotide ligation assay provides a rapid, reliable, nonisotopic method to detect the mutation responsible for APCR that can rapidly be applied to large population screening.
Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21 patients (26%), including seven missense mutations, four splice-site mutations and two insertions in which six were novel mutations. Among the 21 patients, 15 (71%) had three types of the common missense (G233V, R461C, D707G) and one insertion (1795-1796insA) mutation. The patients had slowly progressive muscle weakness with age of onset of the disease varying from 6 to 52 years, averaging 20.9. The most striking pathologic findings were the presence of lobulated fibers in 14 patients, especially in the advanced stages. Differing from Duchenne and Becker muscular dystrophy, opaque (hypercontracted) fibers were very rarely seen. These findings may be helpful in establishing diagnostic screening strategies in Japanese LGMD patients.
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