Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.
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Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation caused by defective carnitine transport. This disease presents early in life with hypoketotic hypoglycemia or later in life with skeletal myopathy or cardiomyopathy. The gene for this condition maps to 5q31.2-32 and OCTN2, an organic cation/carnitine transporter, also maps to the same chromosomal region. Here we test the causative role of OCTN2 in primary carnitine deficiency by searching for mutations in this gene in affected patients. Fibroblasts from patients with primary carnitine deficiency lacked mediated carnitine transport. Transfection of patient's fibroblasts with the OCTN2 cDNA partially restored carnitine transport. Sequencing of the OCTN2 gene revealed different mutations in two unrelated patients. The first patient was homozygous (and both parents heterozygous) for a single base pair substitution converting the codon for Arg-282 to a STOP codon (R282X). The second patient was a compound heterozygote for a paternal 1-bp insertion producing a STOP codon (Y401X) and a maternal 1-bp deletion that produced a frameshift creating a subsequent STOP codon (458X). These mutations decreased the levels of mature OCTN2 mRNA and resulted in nonfunctional transporters, confirming that defects in the organic cation/carnitine transporter OCTN2 are responsible for primary carnitine deficiency. (+info)
Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees.
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It is usually difficult to localize genes that cause diseases with late ages at onset. These diseases frequently exhibit complex modes of inheritance, and only recent generations are available to be genotyped and phenotyped. In this situation, multipoint analysis using traditional exact linkage analysis methods, with many markers and full pedigree information, is a computationally intractable problem. Fortunately, Monte Carlo Markov chain sampling provides a tool to address this issue. By treating age at onset as a right-censored quantitative trait, we expand the methods used by Heath (1997) and illustrate them using an Alzheimer disease (AD) data set. This approach estimates the number, sizes, allele frequencies, and positions of quantitative trait loci (QTLs). In this simultaneous multipoint linkage and segregation analysis method, the QTLs are assumed to be diallelic and to interact additively. In the AD data set, we were able to localize correctly, quickly, and accurately two known genes, despite the existence of substantial genetic heterogeneity, thus demonstrating the great promise of these methods for the dissection of late-onset oligogenic diseases. (+info)
Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.
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Three hundred million individuals are at risk of infection by schistosomes, and thousands die each year of severe hepatic disease. Previous studies have shown that the intensity of infection by Schistosoma mansoni in a Brazilian population is controlled by a major gene, denoted as SM1. We report here the full results of a genome-wide search that was performed on this population to localise SM1. Two hundred and forty-six microsatellites were used for the primary map, and only one region in 5q31-q33 provided significant evidence of linkage. SM1 was subsequently mapped to this region, which contains several genes encoding cytokines or cytokine receptors which are involved in protection against schistosomes. Three additional regions, 1p22.2, 7q36 and 21q22-22-qter, yielded promising, although not significant, lod-score values. These regions contain candidate genes encoding cytokines or molecules relevant to anti-schistosome immunity. (+info)
Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer.
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To study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction. (+info)
New reciprocal translocation t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia.
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We report a new chromosomal reciprocal translocation t(5;10)(q33;q22) in a 49-year-old man with atypical chronic myeloid leukemia (a-CML) and history of occupational exposure to petroleum products including benzene and other hydrocarbons. The t(5;10) (q33;q22) was found in 94% and 84% of metaphases in peripheral blood and bone marrow cells, respectively. Cytogenetic analysis of single colonies derived from granulocyte-macrophage (CFU-GM), and erythroid (BFU-E) hematopoietic progenitors showed that 88% and 40% of CFU-GM and BFU-E, respectively, had the t(5;10)(q33;q22). In contrast, peripheral blood T-lymphocytes, and cutaneous fibroblasts had normal 46,XY karyotype. Molecular analysis of the t(5;10)(q33;q22) translocation breakpoint is currently underway in order to identify genes located in this region which might provide insights into the pathogenesis of atypical myeloproliferative disorders. (+info)
Adverse effects of activated cytotoxic T lymphocytes on the clinical outcome of nodal anaplastic large cell lymphoma.
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Systemic (nodal) anaplastic large cell lymphoma (ALCL) is a subgroup of T-cell non-Hodgkin's lymphomas with a relatively favorable clinical outcome. Part of systemic ALCLs harbor a genetic aberration (usually the t(2;5)(p23;q35) translocation) containing the anaplastic lymphoma kinase (ALK) gene at 2p23, which results in aberrant expression of the ALK protein. Recently, we have shown that the presence of high percentages of activated cytotoxic T lymphocytes (CTLs) in tumor biopsy specimens of Hodgkin's disease (HD) is associated with a poor prognosis. In the present study, we investigated the prognostic value of percentages of activated CTLs in combination with ALK expression in primary nodal ALCL. Primary nodal biopsies of 42 patients with ALCL were investigated for the percentage of activated CTLs (quantified using Q-PRODIT) and the expression of ALK by immunohistochemistry using monoclonal antibodies (MoAbs) directed against T-cell antigen granzyme B (GrB) and ALK, respectively. These parameters were evaluated for their predictive value regarding progression-free and overall survival time. The presence of a high percentage of activated CTLs (ie, >/=15%) was found to be an unfavorable prognostic marker. In combination with a lack of ALK expression, it was possible to identify a group of patients with a very poor prognosis. In this group, 13 of 16 patients died within 2 years as a result of the disease. Of the remaining 26 patients, only three (all ALK negative) died (P <.0001). Furthermore, the percentage of activated CTLs combined with ALK status appeared to be of stronger prognostic value than the International Prognostic Index (IPI). We conclude that a high percentage of activated CTLs present in biopsy material of patients with primary nodal ALCL is a strong indicator for an unfavorable clinical outcome. The combination of ALK expression and percentage of activated CTLs appears to be more sensitive than the IPI in identifying a group of patients with a highly unfavorable clinical outcome who may be eligible for alternative (high dose) therapy schemes. (+info)
Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr-15.
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Four recent genome-wide screen studies in multiple sclerosis (MS) identified a number of candidate regions for susceptibility genes in addition to the HLA complex in 6p21. However, none of these regions provided formally significant evidence for genome-wide linkage. We have investigated such regions in 46 Swedish multiplex MS families, 28 singleton families, 190 sporadic MS patients and 148 normal controls by parametric and nonparametric linkage and association analysis. One microsatellite marker, in 12q23, provided evidence for association in addition to suggestive transmission distortion and slightly positive linkage. In addition, a marker in 7ptr-15 showed a significant transmission distortion as well as a highly significant score in affected pedigree member analysis, but not quite significant deviations in association analysis. One of three markers in 5p, a region implicated in all four previous studies, showed a weakly positive lod score, but no other evidence of importance. Markers in 2p23, 5q11-13, 6q25, 7q21-22, 11q21-23, 13q33-34, 16p13.2, 18p11.32-23, Xp21.3 provided little or no evidence of importance for MS. In summary, these data support the importance of genome-wide screens in the identification of new candidate loci in polygenic disorders. (+info)
Cytogenetic analysis of sperm chromosomes and sperm nuclei in a male heterozygous for a reciprocal translocation t(5;7)(q21;q32) by in situ hybridisation.
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We have studied the meiotic segregation of a reciprocal translocation t(5;7)(q21;q32) in a male carrier, using the human sperm-hamster oocyte fusion technique and the whole chromosome painting. A total of 296 sperm complements were analysed by dual chromosome painting. The frequencies of alternate, adjacent-1, adjacent-2 and 3:1 segregation were 49.7%, 32.4%, 16.2% and 1.7% respectively. Aneuploidy frequencies for chromosomes not involved in the translocation were determined by FISH on decondensed sperm heads using probes from chromosomes X, Y, 6, 18 and 21. A total of 20,118 spermatozoa was analysed, 10,201 by two-colour FISH (probes for chromosomes 6 and 21) and 9917 by three-colour FISH (probes for chromosomes X, Y, and 18). There was no evidence of an interchromosomal effect, since disomy frequencies were within the range of normal controls. (+info)