Search results for "Phenotype"

2016

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were det…

Differential subcellular expression of P525LFUS as a putative biomarker for ALS phenoconversion

2020

P525LFused-in-Sarcoma ( FUS ) mutation is associated with a specific amyotrophic lateral sclerosis (ALS) phenotype characterized by a juvenile-onset and a severe course.1 This harmful point mutation is located in the nuclear localization signal (NLS) domain at the protein C-terminal.2 Although wild-type FUS protein is expressed almost exclusively in the nucleus, the P525L FUS mutation leads to a protein mislocalization into the cytoplasm3,4 because of its loss of capacity to bind its transporter karyopherin-2 and to be transferred back to the nucleus.3

An siRNA-based screen in C2C12 myoblasts identifies novel genes involved in myogenic differentiation

2017

International audience; AbstractMyogenesis is a highly regulated multi-step process involving myoblast proliferation and differentiation. Although studies over the last decades have identified several factors governing these distinct major phases, many of them are not yet known. In order to identify novel genes, we took advantage of the C2C12 myoblastic line to establish a functional siRNA screen combined with quantitative-imaging analysis of a large amount of differentiated myoblasts. We knocked down 100 preselected mouse genes without a previously characterized role in muscle. Using image analysis, we tracked gene-silencing phenotypes by quantitative assessment of cellular density, myotub…

Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

2020

Abstract The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomali…

Prognostic value of methylator phenotype in stage III colon cancer treated with oxaliplatin-based adjuvant chemotherapy

2017

Abstract Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen. Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survi…

Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance

2017

The cancer stem cell (CSC) hypothesis is an increasingly accepted concept in cancer research that provides a plausible explanation for the considerable phenotypic and molecular heterogeneities observed in hepatocellular carcinoma (HCC) which hampers therapeutic progress. The hypothesis infers that CSCs share functional properties similar to adult stem cells, such as self-renewal and differentiation capacity, and are exclusively responsible for tumor evolution. By definition, CSCs are held responsible not only for tumor initiation and progression but also acquisition of chemoresistance and the fueling of relapse after therapy. Therefore, the CSC model has significant implications both for tr…

BRCA1/2 pathogenic variants in triple-negative versus luminal-like breast cancers: genotype–phenotype correlation in a cohort of 531 patients

2020

Background: Several available data suggest the association between specific molecular subtypes and BRCA1/2 mutational status. Previous investigations showed the association between BRCA1/2 pathogenic variants (PVs) in specific genomic regions and phenotypic variations of cancer relative risk, while the role of PV type and location in determining the breast cancer (BC) phenotypic features remains still unclear. The aim of this research was to describe the germline BRCA1/2 PVs in triple-negative breast cancer (TNBC) versus luminal-like BC and their potential leverage on BC phenotype. Patients & methods: We retrospectively collected and analyzed all clinical information of 531 patients wit…

Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy.

2018

Triple negative breast cancer (TNBC) is a heterogeneous disease with distinct molecular subtypes that differentially respond to chemotherapy and targeted agents. The purpose of this study is to explore the clinical relevance of Lehmann TNBC subtypes by identifying any differences in response to neoadjuvant chemotherapy among them. We determined Lehmann subtypes by gene expression profiling in paraffined pre-treatment tumor biopsies from 125 TNBC patients treated with neoadjuvant anthracyclines and/or taxanes +/- carboplatin. We explored the clinicopathological characteristics of Lehmann subtypes and their association with the pathologic complete response (pCR) to different treatments. The g…

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson's disease based on DJ-1 deficiency

2020

ABSTRACTParkinson’s disease (PD) is a neurodenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, which causes striatal dopamine deficiency. Although most PD cases are sporadic (iPD), approximately 5-10% of all patients suffer from monogenic PD forms caused by highly penetrant rare mutations segregating with the disease in families (fPD). One of the genes linked to monogenic PD is DJ-1. Mutations in DJ-1 cause autosomal recessive early-onset forms of fPD; however, it has been shown that an over-oxidized and inactive for…

A "systems medicine" approach to the study of non-alcoholic fatty liver disease

2016

a b s t r a c t The prevalence of fatty liver (steatosis) in the general population is rapidly increasing worldwide. The progress of knowledge in the physiopathology of fatty liver is based on the systems biology approach to studying the complex interactions among different physiological systems. Similarly, translational and clinical research should address the complex interplay between these systems impacting on fatty liver. The clinical needs drive the applications of systems medicine to re-define clinical phenotypes, assessing the multiple nature of disease susceptibility and progression (e.g. the definition of risk, prognosis, diag- nosis criteria, and new endpoints of clinical trials).…