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Missense Substitutions (missense + substitution)

Distribution by Scientific Domains

Life Sciences	66%
Medical Sciences	33%

Selected Abstracts

In silico analysis of missense substitutions using sequence-alignment based methods,

HUMAN MUTATION, Issue 11 2008
Sean V. Tavtigian
Abstract Genetic testing for mutations in high-risk cancer susceptibility genes often reveals missense substitutions that are not easily classified as pathogenic or neutral. Among the methods that can help in their classification are computational analyses. Predictions of pathogenic vs. neutral, or the probability that a variant is pathogenic, can be made based on: 1) inferences from evolutionary conservation using protein multiple sequence alignments (PMSAs) of the gene of interest for almost any missense sequence variant; and 2) for many variants, structural features of wild-type and variant proteins. These in silico methods have improved considerably in recent years. In this work, we review and/or make suggestions with respect to: 1) the rationale for using in silico methods to help predict the consequences of missense variants; 2) important aspects of creating PMSAs that are informative for classification; 3) specific features of algorithms that have been used for classification of clinically-observed variants; 4) validation studies demonstrating that computational analyses can have predictive values (PVs) of ,75 to 95%; 5) current limitations of data sets and algorithms that need to be addressed to improve the computational classifiers; and 6) how in silico algorithms can be a part of the "integrated analysis" of multiple lines of evidence to help classify variants. We conclude that carefully validated computational algorithms, in the context of other evidence, can be an important tool for classification of missense variants. Hum Mutat 29(11), 1327,1336, 2008. © 2008 Wiley-Liss, Inc. [source]

Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database,,

HUMAN MUTATION, Issue 6 2007
Audrey Petitjean
Abstract The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest. Hum Mutat 28(6), 622,629, 2007. Published 2007 Wiley-Liss, Inc. [source]

Asymmetric cross-regulation between the nitrate-responsive NarX,NarL and NarQ,NarP two-component regulatory systems from Escherichia coli K-12

MOLECULAR MICROBIOLOGY, Issue 2 2010
Chris E. Noriega
Summary The NarX,NarL and NarQ,NarP sensor,response regulator pairs control Escherichia coli gene expression in response to nitrate and nitrite. Previous analysis suggests that the Nar two-component systems form a cross-regulation network in vivo. Here we report on the kinetics of phosphoryl transfer between different sensor,regulator combinations in vitro. NarX exhibited a noticeable kinetic preference for NarL over NarP, whereas NarQ exhibited a relatively slight kinetic preference for NarL. These findings were substantiated in reactions containing one sensor and both response regulators, or with two sensors and a single response regulator. We isolated 21 NarX mutants with missense substitutions in the cytoplasmic central and transmitter modules. These confer phenotypes that reflect defects in phospho-NarL dephosphorylation. Five of these mutants, all with substitutions in the transmitter DHp domain, also exhibited NarP-blind phenotypes. Phosphoryl transfer assays in vitro confirmed that these NarX mutants have defects in catalysing NarP phosphorylation. By contrast, the corresponding NarQ mutants conferred phenotypes indicating comparable interactions with both NarP and NarL. Our overall results reveal asymmetry in the Nar cross-regulation network, such that NarQ interacts similarly with both response regulators, whereas NarX interacts preferentially with NarL. [source]

Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome

NEPHROLOGY, Issue 1 2009
LING QIN
SUMMARY Aim: Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalaemic metabolic alkalosis, significant hypomagnesemia, low urinary calcium, secondary aldosteronism and normal blood pressure. GS is caused by inactivating variants in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl co-transporter. So far, more than 100 variants have been described in the SLC12A3 gene in Gitelman syndrome. Methods: Biochemical parameters in blood and urine were measured and documented. Genomic DNA was extracted from peripheral blood of all patients. Variants were screened for the SLC12A3 and CLCNKB gene by sequencing directly. Reverse-transcription polymerase chain reaction and complementary DNA sequence analysis were performed to confirm deletion or splicing variants. Results: We identified 13 variants in the SLC12A3 gene in 13 Chinese patients, including 10 missense substitutions, two splicing variants, and one deletion/insertion variant. Five novel variants were identified for the first time in patients with Gitelman syndrome. We did not find any variants in the CLCNKB gene. A homozygous Thr60Met carrier suffered from hypothyroidism and received thyroxine replacement therapy. Conclusion: We have identified 13 variants, including five novel variants in the SLC12A3 gene in 13 patients with Gitelman syndrome. T60M is the most frequent variant in our patients. There was no significant correlation between genotype and phenotype in our patients. [source]

Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation in KRT10

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2010
C. Covaciu
Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases.1 EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively.1 Usually, mutations are missense substitutions into the highly conserved ,-helical rod domains of the proteins.2,3 However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described.4,6 [source]