Autoimmunity-Associated LYP-W620 Does Not Impair Thymic Negative Selection of Autoreactive T Cells.

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity.

A Mutation in CALM1 Encoding Calmodulin in Familial Idiopathic Ventricular Fibrillation in Childhood and Adolescence.

OBJECTIVES: This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. BACKGROUND: Although sudden cardiac death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. METHODS: Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. RESULTS: We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.

The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity.

Lat(Y136F) knock-in mice harbor a point mutation in Tyr(136) of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the Lat(Y136F) mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of Lat(Y136F) mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in Lat(Y136F) serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in Lat(Y136F) mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.

Failure to thrive in a girl born into a family affected by familial dysalbuminemic hyperthyroxinemia

Autosomal dominant familial dysalbuminemic hyperthyroxinemia (FDH)is characterized by modified human serum albumin (HSA) inducing asubstantially higher affinity for thyroxine (T4). Histidin or prolinsubstitution on residue R218 produces localized conformationalchanges of HSA creating additional room for T4 binding, leadingto 14-20 fold normal total T4 (TT4) levels. Affected individuals areconsidered euthyroid. Our patient is an 18 months-old swiss girl bornto a mother known for the rare R218P mutation in the HSA gene.She presented with severe failure to thrive (height -2.92 SD, weight-3.6 SD), habitual hip dislocation without anatomical anomaly, latefontanelle closing and protruding ears. Psychomotor development isslightly retarded. Thyroid function testing confirmed extremely high TT4(1446.0 nmol/l) levels, which are similar to her brother's values (1534.4nmol/l and 1757.6 nmol/l respectively). Free T4 seems slightly elevated(26 pmol/l), probably due to methodological reasons. TSH (0.92 mU/l),free T3 (4.4 pmol/l) and thyroxin binding globulin (32 mg/l) are withinthe normal range. Her two half-brothers, affected by the samemutation, are now 18.7 (P1) and 16.6 (P2) years old and wereoriginally described by S. Pannain et al. in 2000. Both werecharacterized by growth retardation (-2.1 and -2.2 SD) before the ageof 4 years. P1 has reached a normal adult height (-0.4 SD) and P2has caught up to normal growth (-0.68 SD) with moderate bonematuration delay. Pubertal development and anterior pituitary functionare adequate. Primary growth and developmental retardation in thefirst years of life with adequate catch-up seem to be a distinctcharacteristic in FDH with R218P mutation. Hip dislocation is typicallyseen in other situations associated to thyroid disorders, like Downsyndrome. These findings might be explained by altered early thyroidhormone utilization in children with FDH.

High prevalence of major cardiovascular risk factors in first-degree relatives of individuals with familial premature coronary artery disease : the GENECARD project

Rapport de synthèse La prévalence de l'hypertension artérielle, d'une dyslipidémie, d'une obésité et d'un tabagisme est élevée chez les patients qui souffrent d' une maladie coronarienne familiale précoce (MC-FP). L? e but de cette étude fut d'investiguer la prévalence de ces facteurs de risque cardiovasculaires au sein des membres d'une famille dont un patient est affecté d'une MC-FP. Nous avons étudié 108 familles différentes dont au minimum 2 frères/soeurs ont survécu à une maladie coronarienne précoce. Cette dernière fut définie par la survenue d'un événement coronarien avant l'âge de 51 ans pour les hommes et 56 ans pour les femmes. Au total, nous avons identifié 222 patients atteints de MC-FP chez qui 158 frères/soeurs, 197 enfants et 94 époux/épouses ne souffraient pas de maladie coronarienne. Ces parents proches furent comparés à un collectif d'individus "contrôles" issus de la population générale. Les frères/soeurs non affectés avaient une prévalence plus élevée d'hypertension artérielle (49% versus 24%, p<0.001), d'hypercholestérolémie (47% versus 34%, p=0.002), d'obésité abdominale (35% versus 24%, p=0.006) et de tabagisme (39% versus 24%, p=0.001) par rapport aux individus issus de la population générale. Parmi les enfants, une prévalence plus élevée d'hypertension artérielle fut identifiée chez les femmes, et une prévalence plus élevée d'hypercholestérolémie et d'obésité abdominale dans les deux sexes par rapport aux contrôles de la population générale. Aucune différence parmi les facteurs de risque cardiovasculaire n'a été observée entre les époux/ épouses et les contrôles. Les frères/soeurs affectés et non affectés par la MC-FP ont également été comparés entre eux. La prévalence des facteurs de risque était similaire dans les 2 groupes, sauf pour le tabagisme, qui avait une prévalence plus élevée chez les frères/sueurs affectés (76% versus 39%, p=0.008). La prévalence de l'hypertension artérielle, de l'obésité, et de la dyslipidémie est également élevée chez les parents de premier degré de patients atteints de MC-FP, mais pas chez leurs époux/épouses. Ces personnes-là requièrent donc une attention médicale particulière en raison d'une vulnérabilité familiale et/ou génétique augmentée aux anomalies métaboliques athérogènes. Dans ces familles, le tabagisme pourrait être le facteur déclenchant de la MC-FP.

Du capitalisme familial au capitalisme financier? : le cas de l'industrie suisse des machines, de l'électrotechnique et de la métallurgie au 20e siècle

L'objectif principal de cette thèse consiste à mettre en évidence la persistance du capitalisme familial en Suisse au cours du 20e siècle, et sa résistance aux capitalismes managérial et financier qui sont censés lui avoir succédé. Pour ce faire, nous avons retenu vingt-deux grandes entreprises du secteur des machines, de l'électrotechnique et de la métallurgie - principale branche de l'industrie suisse pour la période considérée -, pour lesquelles ont été recensés les membres des conseils d'administration et les principaux dirigeants exécutifs pour cinq dates- repère couvrant le siècle (1910, 1937, 1957, 1980 et 2000). Cette thèse s'inscrit dans une démarche pluridisciplinaire qui relève à la fois de l'histoire d'entreprise et de la sociologie des dirigeants, et fait appel à différentes méthodes telles que l'analyse de réseau et l'analyse prosopographique. Elle s'articule autour de trois axes de recherche principaux : le premier vise à mettre en évidence l'évolution des modes de gouvernance dans notre groupe d'entreprises, le second investit la question de la coordination patronale et le troisième a pour but de dresser un portrait collectif des élites à la tête de nos vingt-deux firmes. Nos résultats montrent que durant la majeure partie du siècle, la plupart de nos entreprises sont contrôlées par des familles et fonctionnent sur un mode de coordination hors marché qui repose notamment sur un réseau dense de liens interfirmes, le profil des dirigeants restant dans l'ensemble stable. Si la fin du siècle est marquée par plusieurs changements qui confirment l'avènement d'un capitalisme dit financier ou actionnarial et la mise en place de pratiques plus concurrentielles parmi les firmes et les élites industrielles, le maintien du contrôle familial dans plusieurs entreprises et la persistance de certains anciens mécanismes de coopération nous incitent cependant à nuancer ce constat. - The main objective of this research is to highlight the persistence of family capitalism in Switzerland during the 20th century and its resistance to managerial and financial capitalisms that succeeded. For this purpose, we focus on twenty- two big companies of the machine, electrotechnical and metallurgy sector - the main branch of the Swiss industry for the considered period - whose boards of directors and executive managers have been identified for five benchmarks across the century (1910, 1937, 1957, 1980 and 2000). This thesis relates to business history and elites sociology, and uses different methods such as network analysis and prosopography. It is articulated around three main parts. The aim of the first one is to identify the evolution of corporate governance in our twenty-two enterprises, the second part concentrates on interfirms coordination and the objective of the last one is to highlight the profile of the corporate elite leading our firms. Our results show that during the main part of the century, most of the companies were controlled by families and were characterized by non-market mechanisms of coordination such as interlocking directorates ; moreover, the profile of the corporate elite remained very stable. Although some major changes that took place by the end of the century confirmed a transition towards financial capitalism and more competitive interaction among firms and the corporate elite, the persistence of family control in several companies and the maintaining of some former mechanisms of coordination allow us to put this evolution into perspective.

Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Contribution of major cardiovascular risk factors to familial premature coronary artery disease : the GENECARD project

Résumé: Objectifs: Cette étude relève la prévalence des principaux facteurs de risque cardiovasculaire dans les coronaropathies précoces (P-CAD) familiales, survenant chez au moins deux frères et/ou soeurs d'une même fratrie. Méthodes: Nous avons recruté 213 survivants atteints de P-CAD, issus de 103 fratries, diagnostiqués avant l'âge de 50 ans chez les hommes et 55 ans chez les femmes. La présence ou non d'hypertension, d'hypercholestérolémie, d'obésité et de tabagisme a été documentée au moment de l'événement chez 163 de ces patients (145 hommes et 18 femmes). Chaque patient a été comparé à deux individus de même âge et sexe, chez qui un diagnostic de P-CAD «sporadique» (non familiale) était posé, et à trois individus choisis au hasard parmi la population générale. Résultats: En comparaison de la population générale, les patients atteints de P-CAD sporadique avaient une prévalence supérieure pour 1 'hypertension (29% vs. 14%, p<0.001), le cholestérol (54% vs. 33%, p<0.001), l'obésité (20% vs. 13%, p<0.001) et le tabagisme (76% vs. 39%, p<0.001). Ces facteurs de risque étaient de prévalences similaires, voire supérieures chez les patients atteints de P-CAD familiale (43% [p<0.05 vs. P-CAD sporadiques], 58% [p=0.07], 21% et 72%) respectivement). Seulement 7 (4%) des 163 patients atteints de P-CAD familiale et 22 (7%) des 326 patients atteints de P-CAD sporadique, ne présentaient aucun facteur de risque cardiovasculaire, comparés à 167 (34%) des 489 patients issus de la population générale. Conclusions: Les facteurs de risque cardiovasculaire classiques et réversibles ont une haute prévalence chez les patients atteints de P-CAD familiale. Ce fait rend improbable une contribution génétique prédominante, agissant en l'absence de facteurs de risque. Abstract: Objectives: This study was designed to assess the prevalence of major cardiovascular risk factors in familial premature coronary artery disease (P-CAD), affecting two or more siblings within one sibship. Background: Premature CAD has a genetic component. It remains to be established whether familial P-CAD is due to genes acting independently from major cardiovascular risk factors. Methods: We recruited 213 P-CAD survivors from 103 sibships diagnosed before age ?50 (men) or ?55 (women) years old. Hypertension, hypercholesterolemia, obesity, and smoking were documented at the time of the event in 163 patients (145 men and 18 women). Each patient was compared with two individuals of the same age and gender, diagnosed with sporadic (nonfamilial) P-CAD, and three individuals randomly sampled from the general population. Results: Compared with the general population, patients with sporadic P-CAD had a higher prevalence of hypertension (29% vs. 14%, p < 0.001), hypercholesterolemia (54% vs. 33%, p < 0.001), obesity (20% vs. 13%, p < 0.001), and smoking (76% vs. 39%, p < 0.001). These risk factors were equally or even more prevalent in patients with familial P-CAD (43% [p < 0.05 vs. sporadic P-CAD], 58% [p = 0.07], 21% and 72%, respectively). Overall, only 7 (4%) of 163 of patients with familial P-CAD and 22 (7%) of 326 of patients with sporadic P-CAD had none of these conditions, as compared with 167 (34%) of 489 patients in the general population. Conclusions: Classic, remediable risk factors are highly prevalent in patients with familial P-CAD. Accordingly, a major contribution of genes acting in the absence of these risk factors is unlikely

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.