Explore the vast range of titles available.

Coagulation factor XII has been identified as a potential drug target that could prevent thrombosis without increasing the risk of bleeding. However, human data to support the development of factor XII-directed therapeutics are lacking. To assess the role of factor XII in venous thromboembolism, we examine genetic variation in the coding region of the F12 locus across 703,745 participants in the UK Biobank and NIH All of Us biorepositories. We find that heterozygous carriers of nonsense, frameshift, and essential splice site variants in F12 are protected against venous thromboembolism without an increased risk of bleeding or infection. We also show that F12 variant carriers generally experience a quantitative (type I) defect in circulating factor XII levels, though a subset of participants was also identified with possible qualitative (type II) deficiency. In vitro plasma-based thrombin generation is reduced at factor XII concentrations reflective of those seen in F12 variant carriers. We also show that F12 heterozygous mice are protected against venous thromboembolism and display an intermediate phenotype between wild-type and F12 -null animals. We conclude that heterozygous loss of F12 represents a haploinsufficient state characterized by protection against venous thromboembolism and that therapeutically inhibiting factor XII is likely to be safe and effective. Lowering the levels of coagulation factor XII may prevent thrombosis without increasing the risk of bleeding. Here, Haj et al. use a large human dataset to show that this is the case for people carrying mutations that lower the levels of factor XII.

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP. In a 28-year-old woman with postpartum immune thrombotic thrombocytopenic purpura, plasma exchange was unsuccessful. Near death while receiving vasopressors, she was treated with recombinant ADAMTS13, and the disease abated.

Peter Visscher and colleagues report an analysis to partition the genetic variation for several complex traits onto chromosome segments and find that the variation explained is approximately proportional to the total length of genes included within a chromosome segment. They estimate that ~45%, ~17%, ~25% and ~21% of the phenotypic variation, respectively, for height, body mass index, von Willebrand factor and QT interval is tagged by common SNPs, and they partition this variation by chromosome and chromosome segments. We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ∼45%, ∼17%, ∼25% and ∼21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ∼0.5–1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.

Chronic distal spinal muscular atrophy (Chronic DSMA, MIM * 607088) is a rare autosomal recessive disorder characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of Chronic DSMA gene has been previously mapped to chromosome 11q13 in the 10.3 cM interval defined by loci D11S1889 and D11S1321. By linkage analysis in 12 European Chronic DSMA families, we showed that a disease gene maps to chromosome 11q13.3 ( Z max =6.66 at θ =0.00 at the DSM4 locus) and suggested that this condition is genetically homogeneous. Recombination events allowed us to reduce the genetic interval to a 2.6 cM region, telomeric to the IGHMBP2 gene, excluding this gene as the disease causing gene in Chronic DSMA. Moreover, partial linkage disequilibrium was found between three rare alleles at loci D11S1369, DSM4 and D11S4184 and the mutant chromosome in European patients. Analysis of the markers at these loci strongly suggests that most Chronic DSMA chromosomes are derived from a single ancestor. Refinement of the Chronic DSMA locus will hopefully allow to test candidate genes and lead to identification of the disease-causing mutations.

L'information génétique de tout organisme est contenue dans un stock de chromosomes dont le nombre et la structure sont des caractéristiques propres à l'espèce. Au sein de chaque espèce, chez l'homme notamment, on a décrit de nombreuses anomalies de nombre ou de structure (remaniements chromosomiques). Bien qu'ayant souvent des conséquences pathologiques graves, quelques anomalies présentent des fréquences non négligeables et certaines d'entre elles sont même transmissibles aux générations ultérieures. L'étude du maintien ou de l'évolution de la fréquence de telles anomalies a un double intérêt: le premier, pratique, est de tenter une prévision en matière de Santé Publique; le second, théorique, tend à dégager un modèle pour rendre compte du rôle possible de ces remaniements dans l'évolution. Le modèle défini dans cet article intègre plusieurs causes de variation de fréquence: la mutation (probabilité d'apparition de novo), la sélection (mortalité ou fécondité différentielle des porteurs d'anomalies) et la distorsion de ségrégation (ségrégation non mendélienne des anomalies dans la descendance des porteurs sains). L'un des résultats de ce modèle est de montrer clairement que les processus déterministes comme la sélection ou la distorsion de ségrégation n'ont pu jouer un rôle, dans l'évolution des espèces, qu'en étant associés aux effets de processus stochastiques comme la dérive ou l'effet fondateur. /// The genetic information of any organism is contained in a stock of chromosomes, the number and structure of which are characteristics peculiar to the species. Within each species, and more particularly in man, numerous abnormalities in number or in structure (chromosomal modifications) have been described. Though they often lend to serious pathological consequences, the frequency of some abnormalities is not negligible and some of them even can be transmitted to later generations. The study of the frequency of such abnormalities and its development is interesting for two reasons: first to attempt a forecast which shows the effect on public health; secondly, to construct a model which would account for the possible role of these modifications in evolution. The model described in this article includes several causes which tend to a variation in frequencies: mutation (probability of new cases), selection (differential mortality or fertility of those affected) and segregation-distorsion (non-Mendelian segregation of the abnormalities in the progeny of the healthy carriers). The model shows clearly that determinist processes such as selection or segregation distorsion can only play a part in evolution through their association with stochastic processes such as genetic drift or founder effect. /// La informatión genética de todo organismo está contenida en su dotación de cromosomas cuyo número y estructura constituyen características propias de cada especie. En el seno de cada especie, principalmente en el caso de la especie humana, se han observado numerosas anomalías tanto en el número como en la estructura de los cromosomas (aberraciones cromosómicas). A menudo estas aberraciones acarrean consecuencias patológicas graves, sin embargo algunas de ellas presentan frecuencias que no son despreciables e incluso pueden ser transmisibles a las generaciones siguientes. El estudio de la presencia y evolución de tales anomalías ofrece un doble interés: el primero, práctico, es el de sugerir medidas de previsión en el campo de la Salud Pública; el segundo, teórico, tiende a establecer un modelo que pudiera explicar el papel que estas modificaciones pueden tener en la evolución. En el modelo que se presenta en este artículo se integran varias causas de estas frecuencias: mutación (probabilidad de la aparición de una modificación que no existe en los padres), selección (mortalidad o fecundidad diferencial de los portadores de tales anomalías) y distorsión de la segregación (segrecación de carácter no mendeliano de las anomalías en la descendencia de los portadores sanos). Uno de los resultados de este modelo es el de mostrar claramente que los procesos deterministas como la selección o la distorsión de la segregación no han podido ejercer un papel en la evolución de las especies, sino que en la medida en que estos factores se han asociado a los efectos de procesos estocásticos, como la deriva genético el efecto fundador.