Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903.

Nonsense mutations, which occur in ∼11% of patients with genetic disorders, introduce premature termination codons (PTCs) that lead to truncated proteins and promote nonsense-mediated mRNA decay. Aminoglycosides such as G418 permit PTC readthrough and so may be used to address this problem. However, their effects are variable between patients, making clinical use of aminoglycosides challenging.

Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough.

Premature termination codons (PTC) cause over 10% of genetic disease cases. Some aminoglycosides that bind to the ribosome decoding center can induce PTC readthrough and restore low levels of full-length functional proteins. However, concomitant inhibition of protein synthesis limits the extent of PTC readthrough that can be achieved by aminoglycosides like G418.

Effect of small molecule eRF3 degraders on premature termination codon readthrough.

Premature termination codon (PTC) readthrough is considered a potential treatment for genetic diseases caused by nonsense mutations. High concentrations of aminoglycosides induce low levels of PTC readthrough but also elicit severe toxicity. Identifying compounds that enhance PTC readthrough by aminoglycosides or reduce their toxicity is a continuing challenge.

The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418.

Nonsense mutations constitute ~10% of TP53 mutations in cancer. They introduce a premature termination codon that gives rise to truncated p53 protein with impaired function. The aminoglycoside G418 can induce TP53 premature termination codon readthrough and thus increase cellular levels of full-length protein.

2-Aminothiazole-4-carboxamides Enhance Readthrough of Premature Termination Codons by Aminoglycosides.

Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination.

Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis.

Heterozygous missense mutations in several genes in the WNT5A signaling pathway cause autosomal dominant Robinow syndrome 1 (DRS1). Our objective was to clarify the functional impact of a missense mutation in WNT5A on the skeleton, one of the main affected tissues in RS. We delivered avian replication competent retroviruses (RCAS) containing human wild-type WNT5A (wtWNT5A), WNT5AC83S variant or GFP/AlkPO4 control genes to the chicken embryo limb.

Identification and functional analysis of novel facial patterning genes in the duplicated beak chicken embryo.

Cranial neural crest cells form the majority of the facial skeleton. However exactly when the pattering information and hence jaw identity is established is not clear. We know that premigratory neural crest cells contain a limited amount of information about the lower jaw but the upper jaw and facial midline are specified later by local tissue interactions.

Dual functions for WNT5A during cartilage development and in disease.

Mouse and human genetic data suggests that Wnt5a is required for jaw development but the specific role in facial skeletogenesis is unknown. We mapped expression of WNT5A in the developing chicken skull and found that the highest expression was in early Meckel's cartilage but by stage 35 expression was decreased to background. We focused on chondrogenesis by targeting a retrovirus expressing WNT5A to the mandibular prominence prior to cell differentiation.

Association of the expression of IL-4 and IL-13 genes, IL-4 and IgE serum levels with allergic asthma.

Immune and inflammatory responses mediated by cytokines, play important roles in the pathophysiology of asthma. These responses are associated with overexpression of Th2 cytokines such as IL-4 and IL-13. These two cytokines use common receptors for signaling that lead to identical immunological effects and regulation of the Th1/Th2 balance.

Association between the polymorphisms of IL-4 gene promoter (-590C>T), IL-13 coding region (R130Q) and IL-16 gene promoter (-295T>C) and allergic asthma.

Allergic asthma is a multifactorial disease, influenced by genetic and environmental factors. Recent family-based studies have revealed evidence for linkage of human chromosomes 5q31-33, 12q15-24, 11q13 and 15q23.6 as regions likely to contain genes related to asthma.

Association between the polymorphism of TGF-beta1 gene promoter (-509C>T) and idiopathic chronic urticaria.

Idiopathic Chronic Urticaria (ICU), the most common form (70-80%) of chronic urticaria is supposed to have immune basis causes. It is speculated that the promoter polymorphism of TGF-Beta1 gene may be involved in ICU. This condition is thought to affect at least 0.