Search results for "Nonsense"

2020

X-chromosomal retinitis pigmentosa (RP) frequently is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. We evaluated the potential of PTC124 (Ataluren, TranslamaTM) treatment to promote ribosomal read-through of premature termination codons (PTC) in RPGR. Expression constructs in HEK293T cells showed that the efficacy of read-through reagents is higher for UGA than UAA PTCs. We identified the novel hemizygous nonsense mutation c.1154T > A, p.Leu385* (NM_000328.3) causing a UAA PTC in RPGR and generated patient-derived fibroblasts. Immunocytochemistry of serum-starved control fibroblasts showed the RPGR protein in a dot-like expression pattern along the primary…

Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.

2011

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia,…

Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies

2004

We recently identified mutations in the fukutin related protein (FKRP) gene in patients with congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 2I (LGMD2I). The sarcolemma of these patients typically displays an immunocytochemical reduction of alpha-dystroglycan. In this report we extend these observations and report a clear correlation between the residual expression of alpha-dystroglycan and the phenotype. Three broad categories were identified. Patients at the severe end of the clinical spectrum (MDC1C) were compound heterozygote between a null allele and a missense mutation or carried two missense mutations and displayed a profound depletion of alpha-d…

Rescuing CFTR Protein Function: 1,3,4-oxadiazoles versus 1,2,4-oxadiazoles as readthrough inducing drugs

In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause the absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren (1). We reported a rationale for Ataluren promoted readthrough of PTCs by computational approach and GFP-reporter cell-based assay (2) and the observed enhancement of readthrough activity by some Ataluren derivatives (3, 4). In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren w…

Translational Readthrough Inducing Drugs (TRIDs): a study of biodistribution evaluation in mice models

OXADIAZOLE DERIVATIVES FOR THE TREATMENT OF GENETIC DISEASES DUE TO NONSENSE MUTATIONS

2018

Are disclosed oxadiazole derivatives, their use as medicaments and in particular for the treatment of diseases associated with the presence of a nonsense mutation in the gene or a premature stop codon in the mRNA, pharmaceutical formulation comprising said oxadiazole derivatives and prodrug or mixture thereof and the methods for the preparation of said Oxadiazole derivatives.

Genetic analysis of familial Alzheimer’s disease, primary lateral sclerosis and paroxysmal kinesigenic dyskinesia: a tool to uncover common mechanist…

2021

Tesis doctoral 270 p. figuras y tablas

Identification of a new nonsense mutation (Tyr129Stop) of the SRY gene in a newborn infant with XY sex-reversal.

2004

Point mutations and deletions of SRY gene have been described in several cases of XY gonadal dysgenesis. To date, most of these mutations affect the HMG domain of SRY which plays a central role in DNA binding activity of SRY. We report on a non-mosaic XY sex-reversed newborn girl (completely female external genitalia). The direct sequencing of SRY showed a new nonsense mutation in a codon of SRY gene flanking the 3' end of the HMG domain: a thymine is replaced by a guanine at position +387 in codon 129, resulting in the replacement of the amino acid tyrosine (TAT) by a stop codon (TAG). The new mutation of this patient provides further evidence to support the functional importance of the pu…

RESCUE OF LRBA GENE EXPRESSION IN PRIMARY HUMAN FIBROBLASTS CHARACTERISED BY NONSENSE MUTATION c. 5047 (C>T).

2021

Primary immunodeficiencies (PIDs) are rare genetic diseases characterized by susceptibility to infections, increased risk of autoimmunity, hypogammaglobulinemia, and lymphoproliferative syndromes. PIDs are associated to genetic alterations in about 400 known genes, among which, mutations of the LRBA gene. LRBA gene encodes a widely expressed multi-domain protein with highly conserved BEACH domain, involved in regulation of endosomal trafficking, particularly endocytosis of ligand-activated receptors. It was reported that stop mutations affect this gene leading to the loss of the protein expression. Recently, we identified three Translational Readthrough Inducing Drug (TRID), that showed hig…

PTC124-mediated translational readthrough of a nonsense mutation causing Usher syndrome type 1C.

2011

We investigated the therapeutic potential of the premature termination codon (PTC) readthrough-inducing drug PTC124 in treating the retinal phenotype of Usher syndrome, caused by a nonsense mutation in the USH1C gene. Applications in cell culture, organotypic retina cultures, and mice in vivo revealed significant readthrough and the recovery of protein function. In comparison with other readthrough drugs, namely the clinically approved readthrough-inducing aminoglycoside gentamicin, PTC124 exhibits significant better retinal biocompatibility. Its high readthrough efficiency in combination with excellent biocompatibility makes PTC124 a promising therapeutic agent for PTCs in USH1C, as well a…