Deletion mapping indicates that MTS1 is the target of frequent deletions at chromosome 9p21 in paediatric acute lymphoblastic leukaemias

Recent reports have indicated a high frequency of deletions of MTS1 ( CDKN2, p16^ink4, CDKI4 ) in acute lymphoblastic leukaemias (ALLs). This gene is located at chromosome 9p21 and encodes an inhibitor of cyclin D-dependent kinases. In contrast with the observations in some other malignancies, no inactivation of MTS1 by intragenic mutation was demonstrated in leukaemias. A contribution of MTS1 alterations to leukaemogenesis therefore remains questionable. In order to test for the implication of MTS1 as a tumour suppressor gene in paediatric ALLs we have explored the 9p21 chromosomal region in 46 children with this disease. The copy number of the MTS1 gene in blasts from the patients was determined using a quantitative PCR assay enabling us to precisely detect mono- and bi-allelic deletions. Rearrangements of the gene were sought by Southern blot analysis. The extent of the deletions was studied using microsatellite markers spanning the 9p21 chromosomal region. Point mutations were sought in exon 1 and exon 2 of the MTS1 gene in patients with a mono-allelic deletion. In addition, exon 2 of MTS1 , which contains two-thirds of the coding region, was sequenced in all patients who had no deletion of the gene. Altogether, our data are consistent with the view that MTS1 is the target of 9p21 deletions. Either one or two alleles of the gene were deleted in 36% of non-selected children with B-lineage ALL and both alleles were deleted in all seven patients we studied with T-lineage ALL. The absence of any point mutation implies that the major mechanism of inactivation of MTS1 in ALLs is deletional.     

Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Negative (or purifying) selection is the natural process by which deleterious alleles are selectively purged from the population (1). In diploid species, the strength of negative selection at a given locus is predicted to increase with decreasing fitness and increasing dominance of the genetic variants controlling traits: Variation causing early death in the heterozygous state are the least likely to be transmitted to the next generation, as their carriers have fewer offspring than noncarriers (2). Human genetic variants that cause severe diseases are, thus, expected to be the primary targets of negative selection, particularly for diseases affecting heterozygous individuals. In humans, several studies have ranked protein-coding genes according to their levels of negative selection (3–5). Nevertheless, the extent to which negative selection affects human disease-causing genes, and the factors determining its strength, remain largely unknown, particularly because our knowledge of the severity, mode, and mechanism of inheritance of the corresponding human diseases remains incomplete (3, 6–8).The strength of negative selection at a given gene has been traditionally approximated by comparing the coding sequence of the gene in a given species with that of one or several closely related species; it depends on the proportion of amino acid changes that have accumulated during evolution (9–11). With the advent of high-throughput sequencing, intraspecies metrics have been developed, based on the comparison of the probability of predicted loss-of-function (pLOF) mutations for a gene under a random model with the frequency of pLOF mutations observed in population databases (5, 12, 13), which capture the species-specific evolution of genes. Using an interspecies-based method and a hand-curated version of the Online Mendelian Inheritance in Man (hOMIM) database, a previous study elegantly showed that most human genes for which mutations cause highly penetrant diseases, including autosomal dominant (AD) diseases in particular, evolve under stronger negative selection than genes associated with complex disorders (6). However, other studies based on OMIM genes have reported conflicting results (3, 14–17), probably due to the incompleteness and heterogeneity of the datasets used. Moreover, no study has yet addressed this problem with intraspecies metrics, even though it has been suggested that the choice of the reference species for interspecies metrics contributes to discrepancies across studies (6).We aimed to improve the identification of the drivers of negative selection acting on human disease-causing genes, by developing a negative selection score combining several informative intraspecies and interspecies statistics, focusing on inborn errors of immunity (IEI). IEI, previously known as primary immunodeficiencies (18), are genetic diseases that disrupt the development or function of human immunity. They form a large and expanding group of genetic diseases that has been widely studied, and they are well characterized physiologically (immunologically) and phenotypically (clinically) (19–21). IEI are often symptomatic in early childhood, and at least until the turn of the 20th century and the introduction of antibiotics, most individuals with IEI probably died before reaching reproductive maturity. Accordingly, IEI genes have probably been under strong negative selection from the dawn of humankind until very recently. In this study, we investigated whether the severity of IEI and their mode and mechanism of inheritance have left signatures of negative selection of various intensities in the corresponding human genes. Furthermore, we validated our model on genes underlying inborn errors of neurodevelopment (IEND), another group of well-characterized severe genetic diseases.     

Insulin sensitivity and beta-cell function in protease inhibitor-treated and -naive human immunodeficiency virus-infected children

Previous pediatric studies have failed to demonstrate a clear association between protease inhibitor (PI) therapy and abnormal glucose homeostasis in HIV-infected children. To define more precisely the impact of PI therapy on glucose homeostasis in this population, we performed the insulin-modified frequent-sampling iv glucose tolerance test on 33 PI-treated and 15 PI-naive HIV-infected children. Other investigations included fasting serum lipids; glucose, insulin, and C-peptide; single-slice abdominal computed tomography; and, in a subset of PI-treated children, an oral glucose tolerance test.There were no differences between the two groups with respect to fasting serum insulin or C-peptide, homeostatic model assessment insulin resistance, or quantitative insulin sensitivity check index. The mean insulin sensitivity index of PI-treated and PI-naive children was 6.93 +/- 6.37 and 10.58 +/- 12.93 x 10(-4)min(-1) [microU/ml](-1), respectively (P = 0.17). The mean disposition index for the two groups was 1840 +/- 1575 and 3708 +/- 3005 x 10(-4)min(-1) (P = 0.013), respectively. After adjusting for potential confounding variables using multiple regression analysis, the insulin sensitivity index and disposition index of PI-treated children were significantly lower than that of PI-naive children (P = 0.01 for both). In PI-treated but not PI-naive children, insulin sensitivity correlated inversely with visceral adipose tissue area (r = -0.43, P = 0.01) and visceral to sc adipose tissue ratio (r = -0.49, P = 0.004). Mildly impaired glucose tolerance was noted in four of 21 PI-treated subjects tested.Our results demonstrate not only that PI therapy reduces insulin sensitivity in HIV-infected children but also that it impairs the beta-cell response to this reduction in insulin sensitivity and, in a subset of children, leads to the development of impaired glucose tolerance. The presence of insulin resistance, dyslipidemia, and the significant correlation of reduced insulin sensitivity with increased visceral adipose tissue content suggest that PI-containing highly active antiretroviral therapy is associated with the emergence of early features of a metabolic syndrome-like phenotype.     

T-wave alternans for risk stratification and prevention of sudden cardiac death

Despite considerable progress in the management of ischemic heart disease, a substantial proportion of patients continue to experience life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation Trial 2 has recently shown the superiority of implantable cardioverter defibrillators (ICDs) over conventional strategies to prevent sudden death in patients with reduced ejection fraction, but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. T-wave alternans (TWA), which reflects alternation of cellular repolarization, results in a substantial increase in dispersion of repolarization, a prerequisite for reentrant arrhythmias. Recent trials, cumulating close to 3000 patients, have established TWA analysis as a powerful tool for arrhythmia prevention. Based on the most recent estimates, at least one third of post-myocardial infarction patients are expected to be tested negative. With a negative predictive value greater than 90%, TWA might allow for targeting of patients most likely to benefit from ICD therapy. Accurate identification of high-risk patients by noninvasive TWA may allow for improved widespread screening for sudden death prevention in the general population.     

Nephrocalcinosis: initial manifestation of primary Sjögren's syndrome

INTRODUCTION: Nephrocalcinosis is a rare complication of chronic tubulointerstitial nephritis observed in primary Sj?gren's syndrome. It can precede subjective sicca symptoms. OBSERVATION: We report the case of a 50-year-old woman who presented with a primary Sj?gren's syndrome. The first symptoms appeared 10-years-ago while she was affected with a nephrocalcinosis. CONCLUSION: Autoimmune investigations for Sj?gren's syndrome should be initiated in any patient presenting with nephrocalcinosis and distal renal tubular acidosis.     

Celiac disease and autoimmune diseases or systemic disease. Six cases and a review of the literature

BACKGROUND: Celiac disease is an autoimmune disorder which may be associated with another autoimmune or systemic disease. OBJECTIVE: To determine the links between autoimmune diseases and celiac disease. PATIENTS AND METHODS: Among 31 patients with a celiac disease, we selected those who had another autoimmune or systemic disease. RESULTS: We report 6 patients with such disease association: 3 with autoimmune thyroiditis including one also with Grave's disease, 2 with systemic lupus erythematosus including one also with insulin-dependent diabetes mellitus, and 1 with temporal arteritis. CONCLUSION: The link between celiac disease and autoimmune thyroiditis or insulin-dependent diabetes mellitus seems to be real but many discrepancies are observed for the other autoimmune diseases. After a literature review, we suggest a summary of effective associations between celiac disease and autoimmune or systemic diseases.     

Current anatomical and etiological aspects of chronic or subacute, surgical, pure mitral valve insufficiency in adults. Apropos of 75 medicosurgical cases

Seventy five medico-surgical cases (52 men, with a mean age at surgery of 59, and 23 women, with a mean age at surgery of 59) collected between 1983 and 1989, in an ethnically homogeneous and geographically stable population (West Brittany) confirmed that the current anatomical and etiological aspects of chronic (or subacute) pure mitral incompetence (MI) have changed radically. While rates for bacterial and ischemic etiologies remain stable, the share of rheumatic MI (14 cases) has fallen considerably, to the advantage of degenerative MI (51 cases) with a heavy male predominance (39 men) with in 33 cases rupture of the main chordae, and tending to affect the lesser mitral cusp more often. A precise diagnosis in terms of lesions and etiology is possible in almost all cases on the basis of clinical history and echocardiographic findings. In a perfectly homogeneous population, chronic surgical pure MI is currently essentially a male disease, of dystrophic origin, in patients in the 6th and 7th decades of life.     

Anterior infarction of the left ventricle and infarct of the posterior wall of the right ventricle caused by thrombosis of the anterior interventricular artery

The association: anterior infarction of the left ventricle-posterior infarction of the right ventricle, is a rare entity. The authors report the case of a 64 year-old woman, who died on the fifth day of an extended anterior myocardial infarction, present on electrocardiograms; there were however immediate signs of right heart failure unexplained by a pericardial effusion. At the autopsy, the unusual length and distribution of the anterior interventricular artery which was completely obstructed near its origin by a thrombosis occurring on a severe atheromatous and calcified stenosis, explain this association.