PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase-independent manner via a PLC pathway

International audienc

Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease

Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation

Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response

Nephronophthisis

Nephronophthisis (NPH) is an autosomal recessive disease characterized by a chronic tubulointerstitial nephritis that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form). In the juvenile form, a urine concentration defect starts during the first decade, and a progressive deterioration of renal function is observed in the following years. Kidney size may be normal, but loss of corticomedullary differentiation is often observed, and cysts occur usually after patients have progressed to end-stage renal failure. Histologic lesions are characterized by tubular basement membrane anomalies, tubular atrophy, and interstitial fibrosis. The infantile form is characterized by cortical microcysts and progression to end-stage renal failure before 5 years of age. Some children present with extrarenal symptoms: retinitis pigmentosa (Senior-Løken syndrome), mental retardation, cerebellar ataxia, bone anomalies, or liver fibrosis. Positional cloning and candidate gene approaches led to the identification of eight causative genes (NPHP1, 3, 4, 5, 6, 7, 8, and 9) responsible for the juvenile NPH and one gene NPHP2 for the infantile form. NPH and associated disorders are considered as ciliopathies, as all NPHP gene products are expressed in the primary cilia, similarly to the polycystic kidney disease (PKD) proteins

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Electronic health records for the diagnosis of rare diseases

International audienceWith the emergence of electronic health records, the reuse of clinical data offers new perspectives for the diagnosis and management of patients with rare diseases. However, there are many obstacles to the repurposing of clinical data. The development of decision support systems depends on the ability to recruit patients, extract and integrate the patients' data, mine and stratify these data, and integrate the decision support algorithm into patient care. This last step requires an adaptability of the electronic health records to integrate learning health system tools. In this literature review, we examine the research that provides solutions to unlock these barriers and accelerate translational research: structured electronic health records and free-text search engines to find patients, data warehouses and natural language processing to extract phenotypes, machine learning algorithms to classify patients, and similarity metrics to diagnose patients. Medical informatics is experiencing an impellent request to develop decision support systems, and this requires ethical considerations for clinicians and patients to ensure appropriate use of health data

Childhood sexual abuse and adult binge drinking among Kanak women in New Caledonia.

International audienceThe long-term consequences of violence against women are poorly documented within the context of political domination, economic inequalities and rapid social change of indigenous communities. Using data from the first population study on violence against women and their consequences on health in New Caledonia, South Pacific, this article investigates the association between childhood sexual abuse and binge drinking among 441 adult Kanak women. Face-to-face standardised interviews were conducted in 2002-2003, among women aged 18-54 years drawn from the electoral rolls. Childhood sexual abuse before 15 years of age was reported by 11.6% of respondents. Nearly all the perpetrators (96%) were known to the victims (63% being a close relative). The rate of frequent binge drinking amongst the women within the last 12 months was 34%. After controlling for social and demographic factors, an independent association was found between childhood sexual abuse and current binge drinking. This study is the first to analyse the contribution of childhood sexual abuse to the likelihood of later heavy alcohol use in an indigenous population in the South Pacific. The findings call for improving and giving priority to care for children who are victims of violence to prevent long-term health consequences and to develop prevention programs aimed at alcohol-related behaviour in women, while taking into account simultaneous individual and collective factors

Childhood sexual abuse and adult binge drinking among Kanak women in New Caledonia

The long-term consequences of violence against women are poorly documented within the context of political domination, economic inequalities and rapid social change of indigenous communities. Using data from the first population study on violence against women and their consequences on health in New Caledonia, South Pacific, this article investigates the association between childhood sexual abuse and binge drinking among 441 adult Kanak women. Face-to-face standardised interviews were conducted in 2002-2003, among women aged 18-54 years drawn from the electoral rolls. Childhood sexual abuse before 15 years of age was reported by 11.6% of respondents. Nearly all the perpetrators (96%) were known to the victims (63% being a close relative). The rate of frequent binge drinking amongst the women within the last 12 months was 34%. After controlling for social and demographic factors, an independent association was found between childhood sexual abuse and current binge drinking. This study is the first to analyse the contribution of childhood sexual abuse to the likelihood of later heavy alcohol use in an indigenous population in the South Pacific. The findings call for improving and giving priority to care for children who are victims of violence to prevent long-term health consequences and to develop prevention programs aimed at alcohol-related behaviour in women, while taking into account simultaneous individual and collective factors.New Caledonia South Pacific Indigenous women Childhood sexual abuse Binge drinking Kanak women Alcohol