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The significance of genetic factors contributing to the complex etiology of coronary heart disease is discussed using lipoprotein metabolism as an example. A radiochemical screening method was developed fro precise biochemical diagnosis of autosomal monogenic hypercholesterolemia. In this method lymphocytes are used as test material.
Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-100 (FDB) are the two major causes of monogenic primary hypercholesterolaemia. In this review, FH and FDB are defined in relation to normal lipoprotein metabolism. In South Africa FH affects about 1% of Afrikaners, Jews and Indians, while FDB is probably a much rarer disorder. In Afrikaners, three 'founder' mutations are responsible for more than 80% of FH. The population genetics that created the exceptionally high frequency of FH and comparatively low frequency of FDB in various South African populations are described. The genetic organisation and itinerary of the normal low-density lipoprotein (LDL) receptor are reviewed, with particular emphasis on the structure-function relationships in the LDL receptor that have been clarified by the mutations found in South Africa. Finally, the clinical relevance of research into FH in South Africa is discussed.
The samples presented by 67 pedigrees ascertained from the Kirghiz population via proband having an early myocardial infarction were analysed for ischemic heart disease. It is shown that these pathologies are not accompanied by high increase in the cholesterol level, as is usual for the European populations. Segregation analysis of the cholesterol level was performed and a possibility of monogenic control of this trait was demonstrated.
The main goal of this study was to determine and characterise the types of mutations in two monogenic human disorders: cystic fibrosis (CF) and Duchenne/Becker muscular dystrophy (DMD, BMD) and the susceptibility allele frequency in a polygenic disease: type I insulin-dependent diabetes mellitus (IDDM). After analysing 220 chromosomes for mutations in the CF (Cystic Fibrosis Transmembrane Conductance Regulator = CFTR) gene, delta F508 mutation was most abundant (41%) and out of the non-delta F508 CF mutations 5% was identified as G542X, G551D, R553X, N1303K and W1282X. The CF haplotype analysis by using linked markers to the CFTR gene revealed that the CF "B" haplotype occurred in 66.7% of patients, and this haplotype was 57.2% in patients carrying the delta F508 mutation. Prenatal genetic diagnosis for CF was performed in 10 fetuses: 3 were affected, 6 were carriers, and 1 without any CF mutation. Fifty % of 66 patients with DMB/BMD muscular dystrophy had one or more exon deletions in the dystrophin gene. Eighty-five % of the deletions occurred at the 3' and 15% at the 5' end of the gene. Out of the three prenatal diagnosis in one case DMD was substantiated. Thirty-six % of 50 patients with IDDM possessed four, 44% three and 20% two susceptibility markers in the HLA-DQA1, -DQB1 region. The onset of the disease correlated with the number of susceptibility alleles.
Schematically, gene identification can be achieved by functional cloning, based on preexisting knowledge about the basic biochemical defect, positional cloning, initiated by the mapping of the responsible gene to its correct location on a chromosome, or by a combination of these two approaches called "candidate gene" approach. Genes of numerous monogenic hereditary renal disorders have been identified during the last few years by one of these approaches, particularly, the PKD1 and PKD2 genes involved in autosomal dominant polycystic kidney disease, as well as the genes encoding different type IV collagen alpha chains, responsible for Alport syndrome. This allows novel insights in the understanding of the pathogenesis of hereditary renal diseases and has opened new areas of genetic diagnosis.
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The H-Tx rat is a genetic model of hydrocephalus for which thereis a poor understanding of the mode of inheritance. Previous studies suggested a polygenicmode of inheritance but the breeding data to supportthis hypothesis have not been reported. In an attempt to clarify the hereditary mode we have analyzed the data from eight generations of H-Tx rats and four generations of cross-matings between H-Tx rats and Sprague-Dawley (SD) rats. In the H-Tx rat colony 113 of 129 random brother-sister matings (87.60%) produced hydrocephalic offspring, with males and females being equally affected. The overall incidence varied greatly with an average of 30. 35%. In matings with more than three litters, all mating pairs yielded hydrocephalic pups. In cross-matings both hydrocephalic and normal H-Tx rats were mated with normal SD rats. No hydrocephalus was observed in the first generation of 124 pups (F1). Subsequent brother-sister matings of F1 animals generated hydrocephalic pups in the F2 generation with a lower incidence (4.67% in hydrocephalic HTx/SD matings and 5.11% in normal HTx/SD matings, respectively) than in the H-Tx rat colony (30.35%). Back-cross-matings between F2 rats and normal H-Tx rats yielded an incidence of hydrocephalus higher than that of the cross-matings but lower than that of the H-Tx colony. These data strongly suggest that the H-Tx rat is a homozygous carrier of an autosomal recessive hydrocephalus gene with incomplete penetrance. Furthermore, the data clearly rule out sex-linked and polygenic modes of inheritance and provide further insight with respect to genetic inheritance of hydrocephalus.
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Certain populations of the mosquitofish, Gambusia affinis, developed high levels of resistance to endrin and other cyclodiene insecticides as a result of inadvertent exposure to agricultural sprays. Genetic crossing studies show that endrin resistance is inherited as a single, autosomal, intermediate gene.
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Presenilin-1 (PS1) mutations account for the greatest portion of early onset familial Alzheimer's disease (FAD) cases. The exact cellular function of PS1 is not known. To date, PS1 mutations have been shown to alter two potential biological roles of the protein, either of which could make neurons more susceptible to neurodegeneration. First, PS1 mutations result in elevated A beta 42/A beta 40 ratios in plasma of FAD patients, in transgenic mice and in transfected cell lines. A beta 42 is the more hydrophobic and most neurotoxic form of the peptide. A common molecular event that has been associated with all of the known early onset FAD genes is the excessive production or accumulation of the A beta peptide in the brain. PS1 mutations have also been found to alter the Notch signalling pathway, but the mechanism by which this may affect neurodegeneration remains to be determined. Future studies will be needed to elucidate whether PS1 mutations lead directly to neuronal dysfunction and degeneration or cause cell death by increasing A beta 42 generation and deposition.
Presenilin-2 (PS2) is one of three genes [amyloid precursor protein (APP), presenilin-1 (PS1) and PS2] shown to cause familial Alzheimer's disease (FAD), and is highly homologous to PS1. Currently demonstrated functions of PS2 include interactions with APP and A beta, and participation in apoptotic pathways. PS2 FAD mutations influence APP processing in a manner predicted to promote amyloid formation and also enhance the proapoptotic effect of wild-type PS2. Other possible functions of PS2 are related to its homology to Notch pathway genes in Caenorhabditis elegans, suggesting it may have a developmental role. PS2-associated AD is the most reminiscent of the sporadic form of the disease in terms of older age of onset and longer disease duration. Since PS2 mutations are incompletely penetrant and age of onset in carriers is highly variable (40-88 years), elucidation of PS2 mechanisms may reveal factors which modify AD and are therapeutically relevant to sporadic AD.
Four new genetic markers for Chrysomya rufifacies, a fly with maternal sex determination, were characterized. The markers include one body colour mutant, black body (bl), and three eye colour mutants, brown eye (br), apricot eye (ap), and red eye (wr). Two of the latter, br and wr, turn out to be sex linked, the others behave as autosomal genes belonging to different linkage groups. wr is a hypomorphic and w an apomorphic mutation of the white gene, w/w is epistatic to br/br and to ap/ap. A preliminary genetic linkage map with the sex realizer F'/f and the loci br and w residing in homomorphic sex chromosomes is established. Evidence is presented that crossing over is absent in the male sex. The possible causes of the spontaneous appearance of mosaics for eye colour observed among individuals heterozygous for recessive genes are discussed.
The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.
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