Home About us Contact
|
Home About us Contact | ||
|
|
||
Severe Mutations (severe + mutation)
Selected AbstractsInsulin-like signalling in neurons controls lifespan in C. elegansJOURNAL OF NEUROCHEMISTRY, Issue 2002C. A. Wolkow Insulin-like signalling controls C. elegans lifespan, development and metabolism. Mutations that weaken this insulin-like signalling pathway extend lifespan. Severe mutations abolishing insulin-like signalling cause animals to arrest development as dauer larvae, a larval form specialized for stress resistance and long-term survival. A number of the genes acting in this pathway have been cloned, including daf-2, which encodes a homolog of vertebrate insulin/IGF-I receptors, and age-1, encoding the C. elegans homolog of the PI(3)K p110 catalytic subunit. In order to identify cells from which insulin-like signalling controls lifespan and development, transgenic animals were constructed which possessed insulin-like signalling only in specific cell types. To achieve this, cell-type specific promoters were used to drive expression of daf-2 or age-1 cDNAs in daf-2(,/,) or age-1(,/,) backgrounds, respectively. By utilizing this strategy, we could restore wild-type daf-2 or age-1 activity only in cells that are capable of expressing each transgene. Restoring insulin-like signalling to the nervous system of daf-2 or age-1 mutants could rescue long lifespan. This result was specific for transgenes restoring insulin-like signalling to the nervous system. Expressing daf-2 or age-1 cDNAs from muscle- or intestinally-restricted promoters was insufficient to rescue lifespan. In contrast, age-1 and daf-2 expression in either neuronal or non-neuronal cell types rescued dauer larval arrest in the mutants. These findings demonstrate that insulin-like signalling pathways in the nervous system control C. elegans lifespan. [source] Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathwayINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2002D. A. LAMMAS Summary Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFN, production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFN, (Fig. 9). At one pole of this spectrum, represented by the complete IFN,R1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFN,R1/2, complete IL-12p40 and complete IL-12R,1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFN, responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited. Figure 9. ,Spectrum of genetic susceptibility to intracellular bacteria. At one pole of this spectrum complete IFN,R deficiencies are found; at the other pole are healthy resistant individuals. Partial IFN,R1 deficiencies, and complete IL-12R,1 and IL-12p40 deficiencies can be positioned in between, albeit closer to the former end of the spectrum, with clinical outcome also depending on pathogen virulence and host compensatory immune mechanism(s). Abbreviations: IFN,R , interferon gamma receptor, IL-12R,1 , interleukin 12 receptor-1 (modified from Ottenhoff et al. (1998)). [source] Novel alternatively spliced endoplasmic reticulum retention signal in the cytoplasmic loop of Proteolipid Protein-1JOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2007Cherie Southwood Abstract Increased awareness about the importance of protein folding and trafficking to the etiology of gain-of-function diseases has driven extensive efforts to understand the cell and molecular biology underlying the life cycle of normal secretory pathway proteins and the detrimental effects of abnormal proteins. In this regard, the quality-control machinery in the endoplasmic reticulum (ER) has emerged as a major mechanism by which cells ensure that secreted and transmembrane proteins either adopt stable secondary, tertiary, and quaternary structures or are retained in the ER and degraded. Here we examine cellular and molecular aspects of ER retention in transfected fibroblasts expressing missense mutations in the Proteolipid Protein-1 (PLP1) gene that cause mild or severe forms of neurodegenerative disease in humans. Mild mutations cause protein retention in the ER that is partially dependent on the presence of a cytoplasmically exposed heptapeptide, KGRGSRG. In contrast, retention associated with severe mutations occurs independently of this peptide. Accordingly, the function of this novel heptapeptide has a significant impact on pathogenesis and provides new insight into the functions of the two splice isoforms encoded by the PLP1 gene, PLP1 and DM-20. © 2006 Wiley-Liss, Inc. [source] Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21-hydroxylase deficiency) in the Spanish populationCLINICAL GENETICS, Issue 2 2002B Ezquieta This study addresses the contributions of gene conversion and a founder effect to the distribution of the two most frequent severe point mutations of the 21-hydroxylase (21OH) gene causing congenital adrenal hyperplasia: the 655G splicing mutation at intron 2, and Gln318Stop in a Spanish population. Direct and indirect analyses of segregated mutant and normal 21OH genes in 200 Spanish families (classic and nonclassic 21OH deficiency) were performed. Both mechanisms were found to contribute to different degrees to the defective investigated alleles. The 655G splicing mutation (62 alleles, 15.5%) seemed to be almost exclusively related to recent conversion events, whereas Gln318Stop (33 alleles, 8.3%) is more likely to be due to the dissemination of remotely generated mutant alleles. Other severe defective alleles, 8 bp-deletion (13 alleles, 3.3%), 306insT (5 alleles, 1.3%), and gene deletions (43 alleles, 11%), as well as the mild mutation Val281Leu (120 alleles, 30%), also appear to be strongly associated with particular D6S273 alleles. Although gene conversion contributes to the generation of severe 21OH alleles, the high frequency of some severe mutations in different geographic areas is consistent with a founder effect. [source] | ||||||||||