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PubMed2001

Screening for mutations in exons encoding the ligand-binding domain of the LDL receptor gene using PCR-CFLP and PCR-SSCP.

Primary hypercholesterolemia includes both monogenic disorders and polygenic conditions. Two well defined monogenic disorders are familial hypercholesterolemia (FH) and familial defective apolipoprotein (apo) B-100 (FDB). Both disorders convey high risk of premature coronary artery disease. FH and FDB are caused by mutations in LDL receptor and apo B-100 genes, respectively. In the present study, mutations in both genes in Thai subjects with primary hypercholesterolemia were screened. For apo B-100 gene, a common mutation R3500Q was screened. This mutation was not observed in the patients (n = 45). For LDL receptor gene, mutations in the exons encoding the ligand-binding domain were screened. By PCR-CFLP analysis, 18 abnormal CFLP patterns in exon 4, the hot spot for mutations, were found in patients (n=45). One of the DNA samples with abnormal CFLP patterns was previously identified and reported as a possible disease-causing mutation, namely D151Y. For the other exons, the screening technique was PCR-SSCP. Abnormal SSCP patterns in DNA samples from patients (n=20) were found as follows, two in exon 3, one in exon 5 and another one in exon 6. Further characterization by DNA sequencing and family studies for these abnormal patterns are underway.

Adult↗

PubMed2003

[Use of molecular biological methods in invasive prenatal genetic diagnosis].

In the past, prenatal cytogenetic analysis was limited by answering times of one to three weeks and lack of exact diagnosis of some structural abnormalities. The number of prenatal analyses of monogenic diseases was small due to lack of knowledge of the gene and the mutation in question. The introduction of molecular biological techniques allows prenatal diagnosis of the most frequent trisomies within one to two days and exact diagnosis of almost all structural abnormalities. The Human Genome Project now allows prenatal diagnosis for most monogenic diseases, and the rapid improvement of the DNA-chip technology will increase the number of prenatal diagnoses even further.

Chromosome Aberrations↗

PubMed1992

[Clinical and genetic studies of Alzheimer-type dementia].

The families of 128 probands with Alzheimer's disease (AD) and senile dementia (SD) were studied. Genetical and mathematical analyses were employed to estimate the clinico-genealogical findings. The genetic factors were found to be likely to make some contribution to the origin of Alzheimer-type dementia (ATD). The proportion of afflicted relatives considerably exceeded that of the above dementia patients. Two genetic models (monogenic and multifactorial) were tested. The limit estimations of genetic similarity between AD and SD manifestations both in the monogenic and multifactorial models denied the fact that there is a common major gene responsible for liability to Alzheimer-type dementias. The common gene modifiers were assumed to exist in AD and SD. In addition to the differences found between the types of inheritance in patients with these disease, the following features are: an oligogenic type of inheritance in SD and a quasi-dominant one with incomplete manifestations of homo- and heterozygotes in AD. Studies into the clinical polymorphism of Alzheimer-type dementias in hereditary cases enabled the authors to establish the genetically determined signs and the environmentally induced signs. The predisposing features (premorbid characteristic traits and specific features of mnemic and intelligence) were identified, which allowed the development of Alzheimer-type dementias to be predicted in 80% of women from hereditarily aggravated families.

Aged↗

PubMed2003

[Epilepsy and genetics].

The inheritance of epilepsy has been known since antiquity. Twin studies have shown that genes are important, particularly in primary generalised epilepsies, although the overall risk of epilepsy in offspring of parent with epilepsy is only approximately 6%. Many different protein structures control the normal activation of a brain neurone, and genes are responsible for the structure of these proteins. Mutations can lead to the characteristic pathological activation of epileptic neurones. Monogenic epilepsies may be related to changes in structures of importance for neuronal activation, e.g. the Na channel, the K channel, the GABA-A receptor, and in an acetylcholine receptor. A mutation has been demonstrated in a gene possibly related to brain development. Most likely, many primary epilepsies are polygenic. Epilepsy is also a part of many other genetic diseases. Susceptibility genes may be of importance for the development of certain epilepsies. De novo mutations may also occur. Studies in families with epilepsy may lead to the discovery of more monogenic epilepsies. Comparison between large populations of patients and controls is necessary in order to identify susceptibility genes in non-familiar epilepsy. The new knowledge of genetic aspects of epilepsy will bring improvements in diagnostics and treatment.

Brain↗

PubMed2003

Fetal cells in maternal blood: state of the art for non-invasive prenatal diagnosis.

In Singapore, 1 in 5 pregnancies occur in mothers > 35 years old and genetic diseases, such as thalassaemia, are common. Current methods for the diagnosis of aneuploidy and monogenic disorders require invasive testing by amniocentesis, chorion villus biopsy or fetal blood sampling. These tests carry a procedure-related risk of miscarriage that is unacceptable to many couples. Development of non-invasive methods for obtaining intact fetal cells would allow accurate prenatal diagnosis for aneuploidy and single gene disorders, without the attendant risks associated with invasive testing, and would increase the uptake of prenatal diagnosis by women at risk. Isolation of fetal erythroblasts from maternal blood should allow accurate non-invasive prenatal diagnosis of both aneuploidies and monogenic disorders. Expression of gamma-globin in maternal erythroblasts and the inability to locate fetal erythroblasts reliably in all pregnancies have prevented its clinical application. In the absence of a highly specific fetal cell marker, enrichment, identification and diagnosis--the 3 components of non-invasive prenatal diagnosis--have clearly defined objectives. Since fetal cells are rare in maternal blood, the sole purpose of enrichment is yield--to recover as many fetal cells as possible--even if purity is compromised at this stage. In contrast, the primary goal of identification is specificity; absolute certainty of fetal origin is required at this stage if the ultimate objective of diagnosis, accuracy, is to be achieved. This review summarises the current state of the art of non-invasive prenatal diagnosis using fetal erythroblasts enriched from maternal blood.

Adult↗

PubMed2003

[Genetics and dilated cardiomyopathy].

Dilated cardiomyopathy is characterised by dilatation associated with ventricular dysfunction and represents the leading cause of cardiac transplantation. The aetiology of dilated cardiomyopathy is either multifactorial (about 70% of cases) with genetic and environmental components or monogenic (about 30% of cases) by autosomal dominant transmission. One of the features of this cardiomyopathy is its very wide range of genetic abnormalities and of its phenotype expression. In the multifactorial forms, several polymorphisms have been associated with the predisposition or with the severity of the phenotype. However, these associations have only been observed in a small number of cases and require further confirmation. In the monogenic forms, many culprit genes and morbid loci have been identified. These genes code essentially the proteins involved in the architecture of the cardiomyocyte suggesting mechanisms of action which still remain largely hypothetical. To improve the management of patients and their relatives, other morbid genes remain to be identified in addition to understanding the precise molecular and physiological mechanisms which trigger the disease.

Cardiomyopathy, Dilated↗

PubMedDate not supplied

[Importance of genetic factors in the pathogenesis of gonadal and postgonadal human infertility].

The infertility is a important health problem, affecting about 10-15% of couples. The important role of genetic factors in pathogenesis of infertility is now increasingly recognized and our knowledge in this field are improved each day. For these reasons we review the most important genetic causes of infertility. In this paper we analyse the genetic implications in gonadal and postgonadal infertility. Gonadal infertility affects both sexes and are characterised by hypergonadotrophic hypogonadism. Gonadal infertility is produced by chromosomal or monogenic mutations. Chromosomal causes are represented by gonosomal aneuploidy and structural chromosomal abnormalities. The monogenic disorders are consequences of a recessive mutations of hormone, hormonal receptor or enzymes genes. Postgonadal infertility is present in men and is the result of some obstructive disorders.

Female↗

PubMed2005

[Autoimmune polyendocrine syndromes and related diseases: pathogenesis and clinical features].

Autoimmune processes are involved in the pathogenesis of diseases of several endocrine organs. There are also syndromes, where autoimmune diseases of multiple endocrine and other organs occur simultaneously. The pathogenesis of certain syndromes belonging to this group has been clarified recently and this made possible the discovery of previously unknown aspects of autoimmunity. In this review the authors present a brief synopsis of the pathogenesis and clinical features of autoimmune polyendocrine syndrome type 1 and the IPEX syndrome that are inherited as monogenic traits. Although the etiology of type 2 autoimmune polyendocrine syndrome and POEMS syndrome are not as well characterized as that of the aforementioned monogenic diseases, considering their clinical importance, the authors summarize the main features of these syndromes, as well.

Humans↗

PubMed2005

[Genetic causes of obesity].

BACKGROUND: Overweight and obesity represent an increasing health problem. Both genetic and environmental factors contribute to the development of obesity. This article summarises the genetic aspects of these conditions. MATERIAL AND METHODS: A literature search was conducted using PubMed and OMIM. Both original and review articles were included. RESULTS AND INTERPRETATION: The genetic influence on body weight is shown by twin and family studies. Environmental changes in recent decades have promoted the development of obesity in individuals at risk because of their genetic composition. Our understanding of the molecular pathways underlying common obesity is limited. During the last decade a handful of monogenic disorders leading to early, severe obesity in humans have been identified. All affect the central regulation of appetite. These conditions are rare, except for mutations in the melanocortin 4 receptor that account for about 5% of morbidly obese patients (BMI > 40 kg/m). The identification of monogenic forms of obesity has contributed valuable insight into the regulation of appetite and development of obesity, although causal treatment only exists for leptin deficiency. In addition, several well defined Mendelian syndromes are associated with overweight and obesity. The molecular genetic cause is known for some of these syndromes, but how appetite and energy balance are affected is still unclear.

Adult↗

PubMed2005

Type 2 diabetes mellitus: from genes to disease.

The development of type 2 diabetes (T2DM) is determined by two factors: genetics and environment. The genetic background of T2DM is undoubtedly heterogeneous. Most patients with T2DM exhibit two different defects: the impairment of insulin secretion and decreased insulin sensitivity. This means that there are at least two pathophysiological pathways and at least two groups of genes that may be involved in the pathogenesis of T2DM. As far as genetic background [corrected] of T2DM is concerned, the disease may be divided into two large groups: monogenic and polygenic forms. In this review, we present genes known to cause rare monogenic forms of diabetes with predominant insulin deficiency (MODY - maturity-onset diabetes of the young, MIDD - maternally inherited diabetes with deafness) and uncommon syndromes of severe insulin resistance. We also describe some of the main approaches used to identify genes involved in the more common forms of T2D and the reasons for the lack of spectacular success in this field. Although major genes for T2DM still await to be discovered, we have probably established a "road map" that we should follow.

Deafness↗

PubMed2005

Screening of APOB gene mutations in subjects with clinical diagnosis of familial hypercholesterolemia.

Monogenic hypercholesterolemia is a group of lipid disorders, most of which have autosomal dominant transmission. Familial defective apoB (FDB) resulting from mutations in the APOB gene is a well-recognized cause of autosomal dominant monogenic hypercholesterolemia (ADMH). However, the frequency of FDB among patients with ADMH is not well established. The aim of our research was to screen for mutations responsible for FDB in subjects with a clinical diagnosis of familial hypercholesterolemia. We studied 408 patients from the Spanish Register of Familial Hypercholesterolemia, proportionally distributed among all Spanish regions. Abnormal SSCP patterns of the APOB gene were checked by DNA sequencing and restriction analysis. Three out of the 408 patients were carriers of the R3500Q mutation, and 2 subjects were carriers of the silent T3552T mutation; in both of these patients functional mutations in the LDL receptor gene were found. We conclude that FDB is not a common cause of ADMH in Spain; the R3500Q mutation is the only mutation in APOB causing FDB, and the LDL receptor binding domain of APOB is highly conserved in the studied sample.

Apolipoproteins B↗

PubMed2006

[Molecular genetics of Parkinson's disease].

The current views on the role of genetic factors in the pathogenesis of Parkinson's disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson's disease are described. The further development of studying genetic bases of Parkinson's disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson's disease.

Chromosome Mapping↗

PubMed1979

Polymorphism of apolipoprotein E. II. Genetics of hyperlipoproteinemia type III.

Apolipoprotein E from human serum shows a genetic polymorphism determined by two autosomal codominant alleles, Apo En and Apo Ed. Homozygosity for the gene Apo Ed (phenotype Apo E-D) results in primary dysbetalipoproteinemia, but only some individuals with this phenotype develop gross hyperlipidemia (hyperlipoproteinemia type III). Vertical transmission of dysbetalipoproteinemia represents pseudodominance due to the high frequency of the gene Apo Ed. Dysbetalipoproteinemia is already expressed in childhood. To assess the influence of other genes on the expression of hyperlipidemia in phenotype Apo E-D, comparative studies were carried out in kindreds of hypercholesterolemic (group A) and normo- or hypocholesterolemic probands with dysbetalipoproteinemia (group B). This demonstrated the occurrence of familial (non-type III) forms of hyperlipidemia in group A but not in group B kindreds. Distribution of lipoprotein phenotypes in five of the group A kindreds was consistent with the occurrence of familial combined hyperlipidemia. Apo E phenotypes and hyperlipidemia segregated independently. It is concluded that primary dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein metabolism, but not a disease. Coincidence in one individual of genes for this specific dyslipoproteinemia with any of the genes for monogenic or polygenic forms of familial hyperlipidemia results in hyperlipoproteinemia type III. Hence hyperlipoproteinemia type III is caused by at least two non-allelic genes and is a polygenic disorder.

Adolescent↗

PubMed1990

[Comparative clinico-genetic studies of senile dementia and Alzheimer's disease].

The families of 128 probands with senile dementia (SD) and Alzheimer's disease (AD) were entered into the study. The correlation between the familial and sporadic cases of the disease was established. A geneticomathematic analysis was employed to estimate the clinicogenealogical findings. Two genetic models (monogenous and multifactorial) were tested. The contribution of the genetic factors to SD and AD liability was assessed. As a result of a comparative clinicogenetic study of SD and AD it was found that there is no doubt about the contribution made by the genetic factors to the origin of the Alzheimer type dementia (ATD). The rate of the afflicted relatives considerably exceeded the population rates of the investigated patterns of dementia. The limit estimations of the genetic similarity between the manifestations of AD and SD, both in the monogenous and multifactorial models, were obtained, which rejects the presence of the common major gene responsible for liability to these patterns of the ATD. It was assumed that AD and SD are characterized by the presence of the common genes modifiers. In addition, the difference was established between the types of inheritance in persons afflicted with these diseases: an oligogenic type of inheritance in SD, a quasidominant type with incomplete penetrance of homo- and heterozygotes in AD.

Adult↗

PubMed1990

Limits to genetic intervention in humans: somatic and germline.

The promise of somatic cell gene therapy is likely to be limited to a narrow range of monogenic hereditary defects. This therapy raises few moral issues. However, extension to the 'improvement' of a normal trait might raise problems, similar to the use of hormones in sports. Another danger is uses that result, like heroic measures to save the premature newborn, in the prolongation of misery and in intolerable expense. The genetic alteration of germline cells, which can already be accomplished in animals, is in principle applicable to all monogenic diseases. Its use in humans is much less acceptable than somatic cell therapy. The objection that it tampers with human evolution is widely cited. However, more important may be the risk of producing a new defect, for risk is much less acceptable in a yet unborn person than in an already ill individual. In addition, the goal of germline therapy could almost always be accomplished more simply and safely by prenatal diagnosis and selective abortion. The highly polygenic nature of the most interesting traits, both behavioural and physical, makes it unlikely that we shall be able to modify them usefully in the foreseeable future by either somatic or germline intervention. Despite this delivery from temptation, public fear of future 'blueprinting' of humans no doubt contributes to a multi-faceted antiscience movement.

Ethics, Medical↗

PubMed1989

[The development of molecular human genetics and its significance for perspectives of modern medicine].

The introduction of molecular human genetics has become a paradigma for the application of genetic engineering in medicine. The main principles of this technology are the isolation of molecular probes, their application in hybridization reactions, specific gene-amplification by the polymerase chain reaction, and DNA sequencing reactions. These methods are used for the analysis of monogenic diseases by linkage studies and the elucidation of the molecular defect causing these conditions, respectively. They are also the basis for genomic diagnosis of monogenic diseases, introduced into the health care system of the GDR by a national project on Duchenne/Becker muscular dystrophy, Cystic Fibrosis and Phenylketonuria. The rapid development of basic research on the molecular analysis of the human genome and genomic diagnosis indicates, that human molecular genetics is becoming a decisive basic discipline of modern medicine.

Child↗

PubMed1978

Hyperlipidemia in a Lebanese community: difficulties in definition, diagnosis and decision on when to treat.

Fasting serum cholesterol and triglyceride levels were measured in 131 randomly selected adult members of a Lebanese Community of Western New York. Mean cholesterol levels (males, 217 mg%; females 234 mg%) were higher than those reported from the Lebanon but similar to those reported in most other populations. Mean triglyceride levels (males, 153 mg%; females, 115 mg%) were higher than those reported in most other populations. Twenty-three subjects were hyperlipidemic on the basis of age and frequency distribution adjusted serum lipid levels above the 90th percentile. Clinical and family studies carried out on 13 of these 23 hyperlipidemic subjects suggested that 77% had monogenic hyperlipidemia and 23% primary non-monogenic hyperlipidemia. A high frequency of familial hypercholesterolemia (minimum estimate 0.7%) was found, in keeping with the high frequency of the disorder in Lebanon. The study serves to emphasize the difficulties in defining hyperlipidemia, in establishing a specific diagnosis in the individual patient, and in distinguishing between optimum and normal serum lipid levels.

Adult↗

PubMed1988

[Preliminary analysis of inheritance of scoliosis].

90 pedigrees (283 individuals) were used for statistical and segregation analysis of scoliosis inheritance. It was shown that inheritance of scoliosis may be described by the monogenic model with incomplete penetrance of heterozygotes, the latter being lower in men than in women. The monogenic model allows to perform correct predictions, the probability of incorrect prediction being about 0.1.

Female↗