Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31-q33 chromosome region.

There is accumulating evidence for the involvement of genetic factors in the human response to malaria infection, mostly based on results obtained in studies of severe clinical malaria. The role of major gene(s) controlling blood parasitemia levels in human malaria has also been detected by means of segregation analysis. To confirm and to localize such gene(s), we performed a sib-pair linkage analysis investigating the role of five candidate chromosomal regions: 6p21 (HLA-tumor necrosis factor region), 2q13-q21 (genes coding for interleukin-1 alpha and beta), 14q11 (locus coding for the alpha chain of T cell antigen receptor), 7q35 (gene cluster for the beta subunit of T cell receptor), and 5q31-q33, which includes several candidate genes and was recently linked to a locus controlling infection levels by Schistosoma mansoni, denoted as SM1. The analysis was carried out on nine families from a southern Cameroon village, and the phenotype under study was blood infection levels with Plasmodium falciparum. No linkage was found with any of the four markers outside the 5q31-q33 region. A trend in favor of linkage was observed in the distal part of the 5q31-q33 region, especially with the marker D5S636 (P < 0.05 using the Monte Carlo P value), which was the marker that provided the highest evidence for linkage with SM1. These results suggest that a locus influencing P. falciparum levels in malaria could be located in the same genetic region as that containing SM1, indicating that the 5q31-q33 region may be critical in the control of different parasite infections.

Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.

Three hundred million individuals are at risk of infection by schistosomes and around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Previously, we reported evidence, based on a segregation analysis in Brazilian pedigrees, that intensity of infection by Schistosoma mansoni was influenced by a major gene, indicating that host genetic factors are probably critical in controlling schistosome infection and disease development. To localize this gene, referred to as SM1, we performed a genome-wide study on 142 Brazilian subjects belonging to 11 informative families Our results show a linkage to only one region, on chromosome 5q31-q33, with maximum two-point lod scores of +4.74 and +4.52 for D5S636 and the colony stimulating factor-1 receptor marker (CSF1R), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. This region contains several candidate genes encoding immunological molecules that were shown to play important roles in human protection against schistosomes.

[Congenital muscular dystrophy with merosin deficiency: clinical, histopathological, immunocytochemical and genetic analysis]. / Dystrophie musculaire congénitale avec déficience en mérosine: analyse clinique, histopathologique, immunocytochimique et génétique.

A selective deficiency of a specific laminin isovariant, merosin made of M, B1 and B2 chains, was found in a series of 17 patients affected with congenital muscular dystrophy (CMD). The merosin deficiency was complete in 15 cases, and almost complete in two cases. An overexpression of the laminin A chain was seen in these biopsies, while B1 and B2 chains were normally expressed. Comparison of the clinical data with a series of 18 "merosin-non deficient" cases showed that the "merosin-deficient" cases were forming a more homogenous group than the "non-deficient" one. Hypotonia, contractures, motor development delay were generally more severe in the "merosin-deficient" series of cases. Moreover, white matter alterations were seen in most cases explored by MRI or scan imaging. A genetic linkage with a 6q2 locus, corresponding to the M chain gene localization, was found in a panel of informative families from French and Turkish origin with "merosin deficient" CMD. "Merosin non-deficient" families did not map on this locus. So, the "merosin-deficient" CMD can be considered as a peculiar entity within the group of Congenital Muscular Dystrophies.

Malignant hyperthermia and central core disease: analysis of two families with heterogeneous clinical expression.

We report two families both presenting with malignant hyperthermia susceptibility and "core" or "core-like" changes in the muscle tissue. Combined analysis of the malignant hyperthermia phenotype and the histochemical findings demonstrates the complexity of their association and highly suggests genetic heterogeneity of malignant hyperthermia and central core diseases.

[Familial forms of schizophrenia. Cytogenetic study]. / Formes familiales de schizophrénie. Etude cytogénétique.

As a preliminary step in the search for chromosomal location of a susceptibility gene predisposing to schizophrenia, cytogenetic screening of patients might be useful. Search for chromosomal aberrations has successfully directed and accelerated the identification of several disease genes, such as the Duchenne muscular dystrophy gene, retinoblastoma, Burkitt's lymphoma and chronic myeloïd leukemia. Although karyotypes abnormalities do not account for a large portion of cases of Schizophrenia, the two candidate regions predisposing to this disease resulted from observation of chromosomal abnormalities. First, the identification of a partial trisomy of the 5q11-q13 region (Basset et al., 1988) led Sherrington et al. (1988) to report a positive linkage with markers localized on the long arm of chromosome 5, which has not yet been replicated (Kauffman et al., 1989; Kennedy et al., 1988; St Clair et al., 1989). Second, on the basis of frequent cytogenetic abnormalities of the sex chromosome (DeLisi, 1985) in addition to epidemiological observations, Crow (1988) suggested that there could be a locus for psychosis within the pseudoautosomal region, a data which has been recently confirmed (Collinge et al., 1991). With the hypothesis that such aberrations could be more frequent among schizophrenics who have at least one affected first-degree relative, we undertook cytogenetic screening on a sample recruited from consecutive psychiatric admissions to a Psychiatric facility (Hôpital Saint Paul) involving patients living in a limited geographical area on the island of La Réunion, a French Department in the Indian Ocean.(ABSTRACT TRUNCATED AT 250 WORDS)

Linkage analysis in spinal muscular atrophy, by six closely flanking markers on chromosome 5.

The proximal spinal muscular atrophies (SMA) represent the second most common autosomal recessive disorder, after cystic fibrosis. The gene responsible for chronic SMA has recently been mapped to chromosome 5q by using genetic linkage studies. Among six markers mapping to this region, five were shown to be linked with the SMA locus in 39 chronic SMA families each containing at least two affected individuals. Multilocus analysis by the method of location score was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for SMA is between loci D5S6 and D5S39. The genetic distances between these two markers are estimated to be 6.4 cM in males and 11.9 cM in females. Since meiosis were informative with D5S39 and D5S6 in 92% and 87% of SMA families, respectively, it is hoped that the present study will contribute to the calculation of genetic risk in SMA families.

Cystic fibrosis in the population of Reunion Island.

The frequencies of the delta F 508 mutation and haplotypes linked to the cystic fibrosis (CF) gene and detected with DNA probes XV-2C and KM-19 have been studied in the population of Reunion Island, a French province located in the Indian Ocean. The deletion was present in 41.3% of CF chromosomes, whereas this proportion is about 70% in the French population. The delta F 508 mutation was associated with the haplotype B defined by the DNA markers XV-2C (allele 1) and KM-19 (allele 2) in 76.4% of CF chromosomes, while this proportion is over 90% in the French population. Founder effect, genetic drift and admixture can explain these differences.

Somatostatin-immunoreactive concentrations in human saliva and in the submandibular salivary glands of the rat. Possible sexual dependence in the human.

Many biologically active polypeptides have been detected either in the submandibular salivary glands (SSG) of the rat, and in the saliva of rats and humans. The present work has investigated the case of somatostatin (SRIF), since salivary data concerning the presence of this peptide are scarce and contradictory. In a group of healthy volunteers, SRIF-immunoreactivity (SRIF-IR) was tested in samples of mixed saliva. Not all the subjects revealed presence of SRIF-IR in saliva. For men, 5 out of 9 were positive (x = 26.40 +/- 10.03 pg/ml), whereas for women only one out of 10 was positive (x = 96.40 pg/ml). SRIF-IR was also determined in male rat submandibular glands from control animals (26.1 +/- 6.3 pg/mg protein, n = 18) and from animals injected one hour before with an alpha 1-adrenergic secretagogue, phenylephrine (27.9 +/- 7.1 pg/mg protein, n = 6). The results show that SRIF-IR is not constantly present in human saliva obtained from a young population, and that its presence apparently seems to differ between the sexes. On the other hand, the fact that SRIF-IR, unlike other peptides, is not modified when the animals are injected with phenylephrine, may simply indicate that the control mechanism of SRIF-IR release is not the same as that affecting other salivary peptides. Further studies must be carried out in order to elucidate the origin and role of salivary SRIF-IR.

Use of a simple method for the Epstein-Barr virus transformation of lymphocytes from members of large families of Réunion Island.

A simple method for the preparation of lymphoblastoid cell lines from small amounts (100 microliter) of frozen whole blood is described. A success score greater than 90% was obtained for EBV transformations using blood samples which had been collected several months before the infection. Due to the simplicity of the technique, up to 80 samples could be processed per day. This technique was used to prepared 242 permanent cell lines from 13 large families from Réunion Island showing blood group H deficiency. These cell lines are now available for genetic studies.

Cryoenzymic studies on myosin subfragment 1: perturbation of an enzyme reaction by temperature and solvent.

The effects of temperature and solvent on myosin subfragment 1 ATPase have been studied. Under all of the conditions used the data could be fitted to the Bagshaw - Trentham pathway: (formula; see text) Ethylene glycol (40%) was used as the cryosolvent ; this makes K1 and k+2 measurable and allows for temperature studies over an extensive temperature range (+35 to -20 degrees C) and thus to reasonably accurate thermodynamic parameters. The following techniques were used: ATP chase (for K1 and k+2); Pi burst (k+2 or k+3 + k-3); single-turnover Pi burst [k0 = k +4K3 /(1 + K3)] absorption stopped flow (k+2 or k+3 + k-3); steady state (k+6 or k0). Myosin provides examples of causes for nonlinear Arrhenius and van't Hoff plots. A temperature-induced structural change is exemplified by a "jump" in an Arrhenius plot of k+2 and "breaks" in van't Hoff plots of K1 and K3. A change in rate-limiting step is illustrated from stopped-flow experiments ( kobsd approximately k+2 at low and approximately k+3 + k-3 at high temperatures) and steady-state experiments (kcat approximately k+6 at low and approximately k0 at high temperatures). A third cause is illustrated by k0: an Arrhenius plot of k0 is nonlinear since there is a break in K3. These studies illustrate the use of temperature perturbation as a way of revealing reaction intermediates and of defining the conditions required for the isolation of a particular intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the two-step binding of ATP to myosin subfragment 1 by the rapid-flow-quench method.

1. The initial steps on the myosin ATPase (EC 3.6.1.3) pathway are taken to be: (formula; see text) A two-step binding for ATP is assumed, but the evidence for it is unconvincing; because of the rapidity of the process unambiguous values for K1 and K2 are not available. 2. We investigated the myosin mechanism by the chemical flow-quench technique. Reaction mixtures containing [gamma-32P]ATP plus myosin subfragment 1 were quenched in unlabelled ATP (ATP chase) or acid (Pi burst). 3. We show that the ATP-chase method can lead directly to unambiguous values for K1 and k+2. 4. The binding process was slowed down by 40% ethylene glycol. It was studied as a function of the ATP concentration. A limiting plateau resulted, showing a two-step binding for ATP, and values for K1 and k+2 were obtained. 5. K1 and k+2 are rather sensitive to the experimental conditions. Ethylene glycol and lowering of the pH decrease both constants, but an increase in KCl concentration increases them. This suggests that the binding of ATP to myosin is of an electrostatic nature. 6. The Pi-burst method can lead directly to k+3 + k-3, but under certain conditions the kinetics are governed by K1 and k+2. This uncertainty of the interpretation of Pi-burst experiments is discussed.