IS IT DOMINANTLY INHERITED Β THALASSAEMIA OR JUST a Β‐CHAIN VARIANT THAT IS HIGHLY UNSTABLE?

Thein, Swee Lay

doi:10.1046/j.1365-2141.1999.01492.x

Cited by 65 publications

(54 citation statements)

References 43 publications

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“…We used 15 diverse eutherian sequences from GenBank and 10 deleterious mutations from ref. 37 (see Tables 4 and 5 and Figs. 5 and 6, which are published as supporting information on the PNAS web site).…”

Section: Phylogeny Of Brca1mentioning

confidence: 99%

Understanding missense mutations in the BRCA1 gene: An evolutionary approach

Fleming

Potter

Ramirez

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

129

107

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The role of missense changes in BRCA1 in breast cancer susceptibility has been difficult to establish. We used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11 and missense changes likely to disrupt gene function, aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation. We used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occur in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues are concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. Investigation of the functional role of missense changes in breast-cancer susceptibility should focus on 38 missense changes in conserved and 3 in rapidly evolving regions of exon 11. breast cancer ͉ exon 11 ͉ gene evolution ͉ missense change ͉ BRCA1 P rotein-truncating mutations distributed across BRCA1 are associated with an increased cumulative lifetime risk of breast (60-80%) and ovarian (20-40%) cancer (reviewed in ref. 1). Known mutations in breast-cancer susceptibility genes have been collated in the Breast Cancer Information Core (BIC) database (2, 3). Nearly half the reported changes in BRCA1 are frameshift mutations and thus expected to be disease associated (2). Most of the rest are missense changes; 323 of these have been reported in 1,735 individual entries. Disease-association status is known for only a fraction of these: in the RING finger domain (4) and the C-terminal region of the protein (5, 6). Case-control and family studies are underpowered to draw conclusions regarding the remainder; these are not highly penetrant alleles (7-9).The BRCA1 gene encodes a 1,863-aa protein with a single large region, exon 11, encoding some 60%. The gene is highly polymorphic, with many common single-base exon changes. Regions interacting with other proteins have been identified, but structural and biochemical properties of the protein remain largely unknown, making it difficult to predict the consequences of any single missense change (10). Available functional assays are time-consuming, expensive, and applicable only to Cterminal mutations (6,11,12). Predictions regarding missense changes can be strengthened by comparative evolutionary analysis to establish whether mutations cluster in conserved regions (13)(14)(15). Such analyses may be particularly helpful in identifying low-penetrance missense changes in functionally important regions. Phylogenetic approaches can also determine whether certain residues have evolved more rapidly than predicted by neutral theory (the ratio of the rate of nonsynonymous to synonymous substitution, , Ͼ1), reflecting the action of positive (diversifying) selection (16,17).The ability to detect conserved (18-20) and rapidly evolving (21, 22) regions in BRCA1 has been limited by the small number of cloned sequences ...

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Section: Phylogeny Of Brca1mentioning

confidence: 99%

Understanding missense mutations in the BRCA1 gene: An evolutionary approach

Fleming

Potter

Ramirez

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

129

107

View full text Add to dashboard Cite

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“…This difference depends on the fact that premature termination codon mutations lying in exons 1 or 2 activate the process of nonsense-mediated mRNA decay, therefore precluding the accumulation of mRNA encoding for truncated peptides. 62 The diagnosis of dominant beta-thalassemia is difficult, because the unstable beta globin chains in peripheral blood are not easily detected, not even by very accurate electrophoretic or chromatographic procedures.…”

Section: Heterozygous Beta-thalassemiamentioning

confidence: 99%

Beta-thalassemia

Cao

Galanello

2010

Genetics in Medicine

692

560

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“…These are, in general, highly unstable (''hyperunstable variants'') and not detectable in the hemolysate. With concomitant excess of free a-chains, they precipitate, forming inclusion bodies, which cause damage to the membrane of erythroid precursors in the marrow and the ineffective erythropoiesis responsible for the thalassemia intermedia phenotype [9,10].…”

Section: Discussionmentioning

confidence: 99%

“…The elongated b-chains are mostly caused by frameshift mutations in the third exon of the respective gene, as can be seen in Table I [ [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In the case we present here, the deletion of one nucleotide (-C) between codons 140 and 141 abolishes the stop codon at codon 147, transferring the termination of translation to the new codon 157.…”

Section: Discussionmentioning

confidence: 99%

Hb Florida: A novel elongated C‐terminal β‐globin variant causing dominant β‐thalassemia phenotype

et al. 2006

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We report here a new frameshift mutation in exon 3 of the b-globin gene, a single nucleotide deletion (-C) in between codons 140/141 (GCC/CTG?GCC/TG), found in an 8-year-old Argentinean girl with clinical picture of thalassemia intermedia. It leads to a b-chain that is elongated to 156 amino acids [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156) Tyr-COOH]. The resulting hemoglobin, which we named Hb Florida, was not detected in peripheral blood; however, erythroid hyperplasia and dyserythropoiesis with large inclusion bodies on methyl violet staining were observed in bone marrow, suggesting that this is a hyperunstable variant producing a dominant b-thalassemia phenotype, since the other b-allele was completely normal. Am. J. Hematol. 81:358-360, 2006. V V C 2006 Wiley-Liss, Inc.

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IS IT DOMINANTLY INHERITED Β THALASSAEMIA OR JUST a Β‐CHAIN VARIANT THAT IS HIGHLY UNSTABLE?

Cited by 65 publications

References 43 publications

Understanding missense mutations in the BRCA1 gene: An evolutionary approach

Understanding missense mutations in the BRCA1 gene: An evolutionary approach

Beta-thalassemia

Hb Florida: A novel elongated C‐terminal β‐globin variant causing dominant β‐thalassemia phenotype

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