Exhaustive Screening of the Acid β-Glucosidase Gene, by Fluorescence-Assisted Mismatch Analysis Using Universal Primers: Mutation Profile and Genotype/Phenotype Correlations in Gaucher Disease

SummaryGaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases now accessible to therapy. Outside the Ashkenazi Jewish community, a high molecular diversity is observed, leaving ∼30% of alleles undetected. Nevertheless, very few exhaustive methods have been developed for extensive gene screening of a large series of patients. Our approach for a complete search of mutations was the association of fluorescent chemical cleavage of mismatches with a universal strand-specific labeling system. The glucocerebrosidase (GBA) gene was scanned by use of a set of six amplicons, comprising 11 exons, all exon/intron boundaries, and the promoter region. By use of this screening strategy, the difficulties due to the existence of a highly homologous pseudogene were easily overcome, and both GD mutant alleles were identified in all 25 patients studied, thus attesting to a sensitivity that approaches 100%. A total of 18 different mutations and a new glucocerebrosidase haplotype were detected. The mutational spectrum included eight novel acid β-glucosidase mutations: IVS2 G(+1)→T, I119T, R170P, N188K, S237P, K303I, L324P, and A446P. These data further indicate the genetic heterogeneity of the lesions causing GD. Established genotype/phenotype correlations generally were confirmed, but notable disparities were disclosed in several cases, thus underlining the limitation in the prognostic value of genotyping. The observed influence of multifactorial control on this monogenic disease is discussed

Maladies de Gaucher et de Fabry : aspects biochimiques et génétiques

Les maladies de Gaucher et de Fabry sont des maladies de surcharge lysosomale dues respectivement au déficit de la glucocérébrosidase et de l’a galactosidase. La maladie de Gaucher, transmise sur le mode autosomique récessif, est plus fréquente dans la population juive ashkénaze. Le clonage du gène a permis la caractérisation de quelques mutations plus fréquentes dont certaines ont une valeur pronostique, en faveur soit du type 1 non neurologique, soit des types 2 et 3 plus sévères. Ces mutations représentent environ 70 % des allèles, les 30 % restants correspondant à des mutations privées. La maladie de Fabry a quant à elle un mode de transmission récessif lié à l’X. Le dépistage des femmes conductrices est donc essentiel pour le conseil génétique dans les familles à risque. Le gène de l’α galactosidase fait l’objet de nombreuses mutations, ne permettant pas l’établissement de corrélations phénotype-génotype fiables. Ces deux maladies, bien caractérisées au plan biochimique et génétique, constituent un modèle parmi les maladies héréditaires pour le développement de thérapies spécifiques

Caractérisation physiopathologique de la glycogénose de type II et développement de différentes approches thérapeutiques sur un modèle murin de la maladie

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

MULTIDIMENSIONAL EVALUATION OF LIVING STANDARD. Territorial dimension. Gaps. Main reasons, effects and possible remedies

The paper contains analyses of regional/county profile and peculiarities with respect to some defining components of the population’s living standard. It approaches issues relating to: a) demographic changes with emphasis on population diminution, natural growth and migration movement in territorial profile; b) current situation of population’s health on counties evaluated based on some mortality and morbidity indicators – on main causes; c) tourist offer on county profile as consumption factor; d) housing conditions and policy in the housing field; e) population incomes distribution by residence and regional environs. The prepared studies make also reference to main explanatory factors, to economic and social implications on medium and long term, as well as to possible directions of action in view of improving flagrant inequalities in the analysed fields.living standard, health, demographic changes