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Glycine Substitutions (glycine + substitution)
Selected AbstractsA single nucleotide polymorphism in the alcohol dehydrogenase 7 gene (alanine to glycine substitution at amino acid 92) is associated with the risk of squamous cell carcinoma of the head and neckCANCER, Issue 12 2010Sheng Wei MD Abstract BACKGROUND: The authors conducted a hospital-based study of 1110 patients with squamous cell carcinoma of the head and neck (SCCHN) and a control group of 1129 patients to replicate the associations reported by a recent, large European study between 2 potentially functional single nucleotide polymorphisms (SNPs) of the alcohol dehydrogenase (ADH) genes, a substitution in ADH1B at amino acid 48 from arginine to histidine (R48H) (reference SNP number [rs]1229984; guanine to adenine [G,A]) and a substitution in ADH7 at amino acid 92 from alanine to glycine (A92G) (rs1573496; cytosine to guanine [C,G]), and the risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: Multivariate logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). False-positive report probabilities (FPRPs) also were calculated for significant findings. RESULTS: The ADH7 A92G GG and combined CG + GG genotypes were associated with a decreased risk of SCCHN (GG: adjusted OR, 0.32; 95% CI, 0.13-0.82; CG + GG: adjusted OR, 0.74; 95% CI, 0.59-0.94; FPRP, .098) compared with the CC genotype. This association was also evident in subgroups of older patients (aged >57 years), men, former smokers, patients with oral cancer, and patients with N) lymph node status (P < .05 for all); however, such associations were not observed for the ADH1B R48H SNP. CONCLUSIONS: The current results support the ADH7 A92G SNP as a marker for the risk of SCCHN in non-Hispanic white populations. Cancer 2010. © 2010 American Cancer Society. [source] Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosaEXPERIMENTAL DERMATOLOGY, Issue 7 2008Ningning Dang Abstract:, Dystrophic epidermolysis bullosa (DEB) is inherited in both an autosomal dominant DEB and autosomal recessive manner RDEB, both of which result from mutations in the type VII collagen gene (COL7A1). To date, 324 pathogenic mutations have been detected within COL7A1 in different variants of DEB; many mutations are clustered in exon 73 (10.74%) which is close to the 39 amino acid interruption region. Dominant dystrophic epidermolysis bullosa usually involves glycine substitutions within the triple helix of COL7A1 although other missense mutations, deletions or splice-site mutations may underlie some cases. In recessive dystrophic epidermolysis bullosa, the mutations include nonsense, splice site, deletions or insertions, ,silent' glycine substitutions within the triple helix and non-glycine missense mutations within the triple helix or non-collagenous NC-2 domain. The nature of mutations in COL7A1 and their positions correlate reasonably logically with the severity of the resulting phenotypes. [source] Y-position cysteine substitution in type I collagen (,1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype,,HUMAN MUTATION, Issue 4 2007Wayne A. Cabral Abstract The most common mutations in type I collagen causing types II,IV osteogenesis imperfecta (OI) result in substitution for glycine in a Gly-Xaa-Yaa triplet by another amino acid. We delineated a Y-position substitution in a small pedigree with a combined OI/Ehlers-Danlos Syndrome (EDS) phenotype, characterized by moderately decreased DEXA z-score (,1.3 to ,2.6), long bone fractures, and large-joint hyperextensibility. Affected individuals have an ,1(I)R888C (p.R1066C) substitution in one COL1A1 allele. Polyacrylamide gel electrophoresis (PAGE) of [3H]-proline labeled steady-state collagen reveals slight overmodification of the ,1(I) monomer band, much less than expected for a substitution of a neighboring glycine residue, and a faint ,1(I) dimer. Dimers form in about 10% of proband type I collagen. Dimer formation is inefficient compared to a possible 25%, probably because the SH-side chains have less proximity in this Y-position than when substituting for a glycine. Theoretical stability calculations, differential scanning calorimetry (DSC) thermograms, and thermal denaturation curves showed only weak local destabilization from the Y-position substitution in one or two chains of a collagen helix, but greater destabilization is seen in collagen containing dimers. Y-position collagen dimers cause kinking of the helix, resulting in a register shift that is propagated the full length of the helix and causes resistance to procollagen processing by N-proteinase. Collagen containing the Y-position substitution is incorporated into matrix deposited in culture, including immaturely and maturely cross-linked fractions. In vivo, proband dermal fibrils have decreased density and increased diameter compared to controls, with occasional aggregate formation. This report on Y-position substitutions in type I collagen extends the range of phenotypes caused by nonglycine substitutions and shows that, similar to X- and Y-position substitutions in types II and III collagen, the phenotypes resulting from nonglycine substitutions in type I collagen are distinct from those caused by glycine substitutions. Hum Mutat 28(4), 396,405, 2007. Published 2007 Wiley-Liss, Inc. [source] Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans,,HUMAN MUTATION, Issue 3 2007Joan C. Marini Abstract Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the pro,1(I) and pro,2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype,phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in ,1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691,823 and 910,964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril,matrix interactions. Recurrences at the same site in ,2(I) are generally concordant for outcome, unlike ,1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In ,2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype,phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events. Hum Mutat 28(3), 209,221, 2007. Published 2006 Wiley-Liss, Inc. [source] Premature arthritis is a distinct type II collagen phenotypeARTHRITIS & RHEUMATISM, Issue 5 2010Peter Kannu Mutations in the gene encoding type II collagen (COL2A1) give rise to a spectrum of phenotypes predominantly affecting cartilage and bone. These chondrodysplasias are typically characterized by disproportionately short stature, eye abnormalities, cleft palate, and hearing loss. It is less recognized that mutations in COL2A1 can also present as degenerative joint disease in the absence of any other phenotypic clues. We report 2 Australian families presenting with an isolated arthritis phenotype, segregating as a dominant trait affecting both large and small joints, prior to age 30 years. Sequencing of COL2A1 in the propositi revealed 2 sequence changes resulting in glycine substitutions in the triple-helical domain of type II collagen. We review the increasing evidence implicating COL2A1 mutations in individuals presenting with isolated degenerative joint disease, aiming to alert physicians who assess these patients to this possibility. The importance of finding a COL2A1 mutation in such patients lies in the subsequent ability to accurately assess recurrence risks, offer early (including prenatal) diagnosis, and provide information regarding the natural history of the condition. Most importantly, it enables at-risk individuals to be identified for implementation of preventative strategies (i.e., weight loss, joint-friendly exercise programs) and early ameliorative management of their condition. 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