UMD-CFTR: A database dedicated to CF and CFTR-related disorders

Bareil, Corinne; Thèze, C.; Béroud, Christophe; Hamroun, Dalil; Guittard, Caroline; René, Céline; Paulet, Damien; Georges, Marie des; Claustres, Mireille

doi:10.1002/humu.21316

Cited by 23 publications

(25 citation statements)

References 44 publications

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“…The corresponding residue N186 of the cystic fibrosis transmembrane regulator (CFTR/ABCC4) has been modeled to contribute to a hydrophilic ring surrounding the enlarging cytoplasmic vestibule of the CFTR anion translo- cation pathway [43]. The CFTR mutation N186K encoding a likely loss-of-function variant has been found in a compound heterozygous cystic fibrosis patient in trans with the most common loss-of-function mutation DF508 (ID:3215 at www.umd.be/CFTR) [44].…”

Section: Discussionmentioning

confidence: 99%

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

et al. 2012

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Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K 1 ] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34 1 erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K 1 leak characteristic of this condition. Am. J. Hematol. 88:66-72, 2013. V

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Section: Discussionmentioning

confidence: 99%

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

et al. 2012

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“…A naturally occurring mutation of the D-loop aspartate residue (to histidine) in the cystic fibrosis conductance regulator is a known cause of cystic fibrosis, but the affect the mutation has on the cystic fibrosis conductance regulator is unknown (32). The D-loop is named for the absolutely conserved aspartate (D) but it has also been referred to as the "dimerization loop" because it is located at the dimer interface.…”

Section: Discussionmentioning

confidence: 99%

An Interaction between the Walker A and D-loop Motifs Is Critical to ATP Hydrolysis and Cooperativity in Bacteriophage T4 Rad50

Rosa

Nelson

2011

Journal of Biological Chemistry

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We propose that the D-loop aspartate functions to stabilize the Walker A asparagine in a position favorable for catalysis. We find that the asparagine is crucially important to the mechanism of ATP hydrolysis by increasing the affinity for ATP and positioning the ␥-phosphate of ATP for catalysis. Additionally, we propose that the asparagine acts as a ␥-phosphate sensor and, through its interaction with the conserved D-loop aspartate, transmits conformational changes across the dimer interface to the second ATP binding site.

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“…29,45 Highlighting the importance of this motif is the fact that six different Signature motif mutations have been identified in the human ABC protein superfamily member, cystic fibrosis conductance regulator (CFTR). 46 These mutations result in cystic fibrosis and cover four out of the five Signature motif residues (S549R, S549I, S549N, G551S, G551D, Q552 K, R553G, and R553Q). The function of the Signature motif and the deleterious nature of these mutations have just begun to be explored.…”

Section: ' Discussionmentioning

confidence: 99%

Functional Evaluation of Bacteriophage T4 Rad50 Signature Motif Residues

Herdendorf

Nelson

2011

Biochemistry

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The repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome, and organisms have evolved a conserved mechanism to facilitate their repair. In eukaryotes, archaea, and some bacteriophage, a complex made up of Mre11 and Rad50 (MR complex), which are a nuclease and ATPase, respectively, is involved in the initial processing of DSBs. Rad50 is a member of the ATP Binding Cassette (ABC) protein superfamily, the members of which contain an important Signature motif that acts in trans to complete the dimeric ATP binding site. To explore the functional relevance of this motif, four of its five residues were mutated in bacteriophage T4 Rad50, and their respective ATPase and nuclease activities were evaluated. The mutations reveal the functional roles of the Signature motif in ATP binding, hydrolysis, and cooperativity. In several mutants, the degree of DNA activation of ATP hydrolysis activity is reduced, indicating that the Signature motif is involved in allosteric signal transmission between the DNA and ATP binding sites of the MR complex. ATP hydrolysis is not required for nuclease activity when the probe is near the beginning of the DNA substrate; however, when an internal probe is used, decreases in ATPase activity have substantial effects on nuclease activity, suggesting that ATP hydrolysis is involved in translocation of the complex. Unexpectedly, the ATP hydrolysis and nuclease activities are not directly correlated with each other, and each mutation appears to differentially affect the exonuclease activity of Mre11. 1 DSBs are common and can be caused by internal and external factors. Internal DNA damaging factors can be metabolic byproducts such as reactive oxygen species or stalled protein complexes that cause collapse of the replication fork. External DNA damaging factors can be UV radiation, ionizing radiation, or a wide range of genotoxic chemicals. In addition to spontaneous DSBs that are considered a form of DNA damage, eukaryotic genomes are subject to programmed DSBs that occur during meiosis or VDJ recombination. 2In eukaryotes, there are three pathways for the repair of DSBs: homologous recombination (HR), nonhomologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). 3NHEJ is considered to be "classic end-joining" and primarily relies on Ku70-Ku80, along with DNA ligase IV and XRCC4. 4 NHEJ can be either error-free or error-prone, the latter of which is due to small deletions or insertions at the site of DNA ligation. 5MMEJ is Ku-independent and is always error-prone as it relies on base-pairing between microhomologies of approximately 5À 25 nts that are exposed by nucleolytic trimming of the DSB. 3HR is considered to be an error-free DSB repair pathway as it uses undamaged homologous DNA as a template for repair of the damaged DNA. 6 The homologous DNA can be a sister chromatid, a homologue (if the organism is mulitploidy), or a homologous sequence on the same or different chromosome. The Mre11/Rad50 (MR) complex is directly involved ...

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UMD-CFTR: A database dedicated to CF and CFTR-related disorders

Cited by 23 publications

References 44 publications

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

An Interaction between the Walker A and D-loop Motifs Is Critical to ATP Hydrolysis and Cooperativity in Bacteriophage T4 Rad50

Functional Evaluation of Bacteriophage T4 Rad50 Signature Motif Residues

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