Pratique de la statistique descriptive

Il s'agit d'un livre d'exercices résolus qui invite le lecteur à réfléchir sur l'usage judicieux de l'outil adéquat, initie à l'analyse des données statistiques et à l'interprétation des résultats obtenus, aborde les techniques statistiques les plus récentes, telles que l'analyse exploratoire des données ou la statistique robuste

A HOX Gene Mutation in a Family with Isolated Congenital Vertical Talus and Charcot-Marie-Tooth Disease

Congenital vertical talus (CVT), also known as “rocker-bottom foot” deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched “claw foot” appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T→A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; θ=0), and it very likely accounts for both CVT and CMT in heterozygotes

Dent Disease with Mutations in OCRL1

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP(2) 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised

Familial dementia caused by polymerization of mutant neuroserpin.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases