Human genetics
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Asthma is a complex disease involving genetic and environmental aetiology. The tumour necrosis factor-alpha (TNF-alpha) and angiotensin-converting enzyme (ACE) genes have been implicated in asthma pathogenesis. This study investigated the association of a G-308A variant of TNF-alpha and an insertion/deletion (I/D) variant of ACE with a self-reported history of childhood asthma, in two population groups. ⋯ The ACE DD genotype was not associated with childhood asthma in either population group. Gametic phase disequilibrium between the TNF-alpha-308 and ACE I/D variants was significantly different from zero in UK/Irish cases (delta=0.09; P=0.034). The TNF-alpha308 allele 2 or a linked major histocompatibility complex (MHC) variant may be a genetic risk factor for childhood asthma in the UK/Irish sample.
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Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are two inherited peripheral neuropathies. The most prevalent mutations are a reciprocal 1.5-Mb duplication and 1.5-Mb deletion, respectively, at the CMT1A/HNPP locus on chromosome 17p11.2. Point mutations in the coding region of the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) or connexin 32 (Cx32) have been reported in CMT patients, including CMT type 1 (CMT1), CMT type 2 (CMT2) and Déjérine-Sottas neuropathy (DS) patients, and only in the coding region of PMP22 in HNPP families lacking a deletion. ⋯ Six out of nine nucleotide substitutions in the Cx32 gene involved two codons encoding arginine at positions 164 and 183, suggesting that these two codons may constitute two Cx32 regions prone to mutate in the Spanish population. Analysis of HNPP patients revealed a 5' splicing mutation in intron 1 of the PMP22 gene in a family with autosomal dominance, which confirms allelic heterogeneity in HNPP. Ectopic mRNA analysis on leukocytes suggests that this mutation might behave as a null allele.
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Studies in vitro have shown that a respiratory-deficient phenotype is expressed by cells when the proportion of mtDNA with a disease-associated mutation exceeds a threshold level, but analysis of tissues from patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) have failed to show a consistent relationship between the degree of heteroplasmy and biochemical expression of the defect. One possible explanation for this phenomenon is that there is variation of heteroplasmy between individual cells that is not adequately reflected by the mean heteroplasmy for a tissue. We have confirmed this by study of fibroblast clones from subjects heteroplasmic for the MELAS 3243 (A-->G) mtDNA mutation. ⋯ There was either no change or a decrease in the variance of intercellular heteroplasmy for the MELAS 3243 mutation, which is most consistent with segregation of heteroplasmic units of multiple mtDNA molecules in mitosis. After mitochondria from one of the MELAS 3243 fibroblast cultures were transferred to a mitochondrial DNA-free (rho0) cell line derived from osteosarcoma cells by cytoplast fusion, the mean level and intercellular distribution of heteroplasmy was unchanged. We interpret this as evidence that somatic segregation (rather than nuclear background or cell differentiation state) is the primary determinant of the level of heteroplasmy.
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Comparative Study
Analysis of crossover type in the alpha -3.7 haplotype among sickle cell anemia patients from various parts of Africa.
The frequency of alpha+-thalassemia has been determined in African populations carrying beta S-chromosomes of different origins. All these alpha+ thalassemias result from a right-ward deletion. Restriction mapping of the alpha -3.7/haplotype with the enzyme ApaI only showed the presence of a type I crossover. RsaI polymorphism at the 5' end of Z alpha 2 is largely represented in the normal population (gene frequency 23%) but, in our series, never associated with the alpha -3.7/haplotype.
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A fragile site on chromosome 12, at 12q24.13, was found in the lymphocytes of two members of a family during the study for detection of a fragile X chromosome. The site was found to be heritable and folate-sensitive, and it fulfills all four criteria for a fragile site. It thus can now be confirmed as the heritable fragile site FRA12C.