Impact of a common mutation of the LDL receptor gene, in French-Canadian patients with familial hypercholesterolemia, on means, variances and correlations among traits of lipid metabolism

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65502/1/j.1399-0004.1995.tb03925.x.pd

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes

Background In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. Methods Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified patients in each postal code area was calculated and visualised in different maps. Results A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. Conclusions Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherland

Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01-0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families

Homozygosity mapping of a third Joubert syndrome locus to 6q23

Background: Joubert syndrome (JS) is a recessively inherited disorder characterised by hypotonia at birth and developmental delay, followed by truncal ataxia and cognitive impairment, characteristic neuroimaging findings (cerebellar vermis hypoplasia, "molar tooth sign") and suggestive facial features. JS is clinically heterogeneous with some patients presenting with breathing abnormalities in the neonatal period, oculomotor apraxia, retinal dystrophy, retinal coloboma, ptosis, hexadactyly, and nephronophtisis or cystic dysplastic kidneys. JS is also genetically heterogeneous, with two known loci, on 9q34 (JBTS1) and 11p11-q12 (CORS2), representing only a fraction of cases. Methods: A large consanguineous Joubert family (five affected) was analysed for linkage with a marker set covering the entire genome and 16 smaller families were subsequently tested for candidate loci. Results: We report here the identification of a third locus in 6q23 (JBTS3) from the study of two consanguineous families. LOD score calculation, including the consanguinity loops, gave a maximum value of 4.1 and 2.3 at q = 0 for the two families, respectively. Conclusions: Linkage between the disease and the D6S1620–D6S1699 haplotype spanning a 13.1 cM interval is demonstrated. Genotype-phenotype studies indicate that, unlike CORS2, JBTS3 appears not to be associated with renal dysfunction

Association between human African trypanosomiasis and the IL6 gene in a Congolese population

Despite the importance of behavioural and environmental risk factors, there are arguments consistent with the existence of a genetic susceptibility to human African trypanosomiasis (HAT). A candidate gene association study was conducted in the Democratic Republic of Congo using a family-based sample which included a total of 353 subjects (86 trios; one case and parents (n = 258) and 23 families with more than one case and parents (n = 95)). Polymorphisms located on the IL1 alpha, IL4, IL6, IL8, IL10, TNF alpha and IFN gamma genes were genotyped after re-sequencing of the genes for extensive SNP search. The T allele of the IL6(4339) SNP was significantly associated with a decreased risk of developing the disease (p = 0.0006) and a suggestive association was observed for the IL1 alpha(5417T) SNP and an increased risk of developing the disease. These results suggest that genetic variability of the IL6 and to a lesser extent the IL1 alpha gene are involved in the development of HAT. For the TNF alpha and IL10 gene polymorphisms, association results obtained here were different from those we observed in another population living under different epidemiologic conditions. This underlines the complexity of the interactions existing between host genetic polymorphisms, parasite diversity and behavioural and environmental risk factors in HAT

Physical and institutional vulnerability assessment method applied in Alpine communities. Preliminary Results of the SAMCO-ANR Project in the Guil Valley (French Southern Alps).

International audienceIn the frame of the SAMCO project designed for mountain risk assessment, our goal is to estimate specific form of vulnerability for communities living in the Upper Guil catchment in order to provide useful documentation for a better management of the valley bottom and the implementation of adequate mitigation measures. Here we present preliminary results on three municipalities of the upper Guil catchment: Aiguilles, Abriès, and Ristolas. We propose an empirical semi-quantitative indicator of potential hazards consequences on element at risk (based on GIS) with an application to different (local and regional scale) scales. This indicator, called Potential Damage Index, enable us to describe, quantify, and visualize direct (physical injury, structural and functional damage on buildings, lifelines and land cover) and indirect (socio-economic impacts) consequences. The method allows estimating the possible damage caused by torrential and gravitational hazards by combining weighted indicators (age, state, land use, number of occupied floors, etc.) reflecting the exposure of elements at risk (land cover, buildings, and lifelines) to obtain different maps of total consequences. Besides, this method allows introducing temporality by modifying the weight and the combination of variables. For example, we can operate the distinction between day and night or between the off-season and the touristic season. Another benefit of this method is to permit the visualization of the vulnerability evolution producing diachronic maps. All these maps, combined with adequate hazards map, will contribute to a better assessment of vulnerability in the Queyras and must help the development of better land use and evacuation plans, and thus are important tools for local authorities. This study will be completed by an analysis of social and institutional vulnerability realized on the basis of interview with local councillors and risk perception survey led with the local populations and the tourists

Physical and institutional vulnerability assessment method applied in Alpine communities. Preliminary Results of the SAMCO-ANR Project in the Guil Valley (French Southern Alps).

International audienceIn the frame of the SAMCO project designed for mountain risk assessment, our goal is to estimate specific form of vulnerability for communities living in the Upper Guil catchment in order to provide useful documentation for a better management of the valley bottom and the implementation of adequate mitigation measures. Here we present preliminary results on three municipalities of the upper Guil catchment: Aiguilles, Abriès, and Ristolas. We propose an empirical semi-quantitative indicator of potential hazards consequences on element at risk (based on GIS) with an application to different (local and regional scale) scales. This indicator, called Potential Damage Index, enable us to describe, quantify, and visualize direct (physical injury, structural and functional damage on buildings, lifelines and land cover) and indirect (socio-economic impacts) consequences. The method allows estimating the possible damage caused by torrential and gravitational hazards by combining weighted indicators (age, state, land use, number of occupied floors, etc.) reflecting the exposure of elements at risk (land cover, buildings, and lifelines) to obtain different maps of total consequences. Besides, this method allows introducing temporality by modifying the weight and the combination of variables. For example, we can operate the distinction between day and night or between the off-season and the touristic season. Another benefit of this method is to permit the visualization of the vulnerability evolution producing diachronic maps. All these maps, combined with adequate hazards map, will contribute to a better assessment of vulnerability in the Queyras and must help the development of better land use and evacuation plans, and thus are important tools for local authorities. This study will be completed by an analysis of social and institutional vulnerability realized on the basis of interview with local councillors and risk perception survey led with the local populations and the tourists

Homozygosity mapping of Marinesco-Sjogren syndrome to 5q31

Marinesco-Sj\uf6gren syndrome (MSS), first described in 1931, is an autosomal recessive condition characterised by somatic and mental retardation, congenital cataracts and cerebellar ataxia. Progressive myopathy was later reported to be also a cardinal sign of MSS, with myopathic changes on muscle biopsies. Hypergonadotrophic hypogonadism and skeletal deformities related to pronounced hypotonia were also reported. The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter. Using homozygosity mapping strategy in two large consanguineous families of Turkish and Norwegian origin, respectively, we have identified the MSS locus on chromosome 5q31. LOD score calculation, including the consanguinity loops, gave a maximum value of 2.9 and 5.6 at theta=0 for the Turkish and the Norwegian families, respectively, indicating linkage between the disease and the D5S1995-D5S436 haplotype spanning a 9.3 cM interval. Patients of the two families presented with the strict clinical features of MSS. On the other hand, the study of two smaller French and Italian families, initially diagnosed as presenting an atypical MS syndrome, clearly excluded linkage from both the MSS locus on 5q31 and the CCFDN locus in 18qter. Patients of the two excluded families had all MSS features (but the myopathic changes) plus peripheral neuropathy and optic atrophy, and various combinations of microcornea, hearing impairment, seizures, Type I diabetes, cerebral atrophy and leucoencephalopathy, indicating that only the pure MSS syndrome is a homogeneous genetic entity