Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing

2007 ◽  
Vol 28 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Michael Krawczak ◽  
Nick S.T. Thomas ◽  
Bernd Hundrieser ◽  
Matthew Mort ◽  
Michael Wittig ◽  
...  
Keyword(s):  
Base Pair ◽  
Mrna Splicing ◽  
Single Base ◽  
Human Genes ◽  
Single Base Pair

Clinical Outcomes for Patients with Severe Chronic Neutropenia Due to Mutations in the Gene for Neutrophil Elastase, ELANE

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3275-3275 ◽  
Author(s):  
Vahagn Makaryan ◽  
Cornelia Zeidler ◽  
Audrey Anna Bolyard ◽  
Julia Skokowa ◽  
Merideth L. Kelley ◽  
...  
Keyword(s):  
Amino Acid ◽  
Base Pair ◽  
Mrna Splicing ◽  
Amino Acid Substitutions ◽  
Median Dose ◽  
Congenital Neutropenia ◽  
Single Base ◽  
Single Base Pair ◽  
Apparent Association ◽  
Chronic Neutropenia

Abstract Abstract 3275 Background: Mutations in the gene for neutrophil elastase, ELANE, are the most common cause of both cyclic (CyN) and congenital neutropenia (CN). Hypothesis: The risk of transformation to AML and effectiveness of G-CSF therapy for CyN and CN are consequences of the specific mutations and types of mutations in ELANE. Methods: We analyzed the treatment responses to G-CSF and occurrence of MDS/AML in 307 patients (CyN 118 and CN 189) with ELANE mutations observed prospectively for 0.4 to 24.9 years through the Severe Chronic Neutropenia International Registry (SCNIR). Most, but not all, patients have received long-term treatment with G-CSF. The median dose in CyN patients was 2.2 μg/kg/day (median duration 14.5 years; mean duration 13.9 years; range: 0.6 – 24.9 years) and the median dose in CN patients was 6.8 μg/kg/day (median duration 10.8 years; mean duration 11 years, range: 0.4 – 24.1 years). Findings: In this population, there are 110 different ELANE mutations: 68 single base pair/amino acid substitutions; 16 frameshifts; 10 terminations; 8 intronic mutations predicted to alter mRNA splicing; and 7 in-frame deletions or insertions. There is also one single-base mutation in the 5' UTR near the start codon. Single base pair/amino acid substitutions are the most common in both CyN and CN populations. Several mutations, particularly in exons 4 and 5 and intron 4, have been observed in both CyN and CN patients. This overlap confounds the use of genetic testing for differential diagnosis of these conditions. Twenty-nine of 189 (15%) CN patients developed MDS/AML, associated with 26 different ELANE mutations. Clusters of MDS/AML cases were observed at two loci: 3 of 4 patients with mutations at C151Y and 3 of 9 patients with mutations at G214R developed MDS/AML. There are 85 mutations which have thus far not been associated with MDS/AML. There is no apparent association of AML with mutations in particular regions of the gene, i.e., specific exons or introns. However, there is an apparent association between type of mutation and risk of leukemia. MDS/AML occurred in decreasing frequency with frameshifts 6/19 (32%); terminations 3/12 (25%); intronic predicted to alter mRNA splicing 3/15 (20%); in-frame deletions or insertions 1/7 (14%); and single base pair/amino acid substitutions 16/136 (12%). The apparent high risk associated with the substitution mutations C151Y and G214R may be attributable to major changes in the protein structure due to the size and charge/polarity differences of the exchanged amino acids. Significantly, there are no cases of CyN associated with MDS/AML and no cases of CyN associated with frameshift mutations. Because of the association of higher G-CSF doses with greater risk of AML, we examined the relationship between G-CSF dose and ELANE genotype. Of 233 patients with available dosing data, 74 received G-CSF doses greater than 8 μg/kg/day; a dose level previously associated with increased risk of MDS/AML (Rosenberg et al, Blood 2008). The ELANE mutations in this sub-population were: frameshifts 9/19 (47%); terminations 6/14 (43%); intronic 4/41 (10%); in-frame deletions or insertions 1/8 (12%); single base pair/amino acid substitutions 53/149 (36%); and 5'UTR 1/1 (100% at 16 μg/kg/day). The median G-CSF doses for these 233 patients were: frameshifts 7.0 μg/kg/day; terminations 5.1 μg/kg/day; single base pair/amino acid substitutions 5.1 μg/kg/day; intronic 2.4 μg/kg/day; in-frame deletions or insertions 5.4 μg/kg/day; 5'UTR 16 μg/kg/day. Conclusions: The association of certain mutations, i.e., C151Y and G214R, and frameshift and termination mutations with higher risk of MDS/AML and higher requirements for G-CSF therapy are important findings that should prove helpful to clinicians and guide further basic research. Registries and repositories are extremely valuable for understanding the consequences of rare hematological diseases such as cyclic and congenital neutropenia. Disclosures: Boxer: Amgen: Equity Ownership. Dale:AMGEN: Consultancy.

Single base-pair substitutions at the translation initiation sites of human genes as a cause of inherited disease

2011 ◽  
Vol 32 (10) ◽  
pp. 1137-1143 ◽  
Author(s):  
Andreas Wolf ◽  
Amke Caliebe ◽  
Nick S.T. Thomas ◽  
Edward V. Ball ◽  
Matthew Mort ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Base Pair ◽  
Inherited Disease ◽  
Single Base ◽  
Human Genes ◽  
Single Base Pair

scholarly journals Overexpression of the MtrC-MtrD-MtrE Efflux Pump Due to an mtrR Mutation Is Required for Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae

2002 ◽  
Vol 184 (20) ◽  
pp. 5619-5624 ◽  
Author(s):  
Wendy L. Veal ◽  
Robert A. Nicholas ◽  
William M. Shafer
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Base Pair ◽  
Efflux Pump ◽  
Penicillin Resistance ◽  
Single Base ◽  
Base Pair Deletion ◽  
Resistance To Penicillin ◽  
Single Base Pair ◽  
High Level ◽  
Level Resistance

ABSTRACT The importance of the mtrCDE-encoded efflux pump in conferring chromosomally mediated penicillin resistance on certain strains of Neisseria gonorrhoeae was determined by using genetic derivatives of penicillin-sensitive strain FA19 bearing defined mutations (mtrR, penA, and penB) donated by a clinical isolate (FA6140) expressing high-level resistance to penicillin and antimicrobial hydrophobic agents (HAs). When introduced into strain FA19 by transformation, a single base pair deletion in the mtrR promoter sequence from strain FA6140 was sufficient to provide high-level resistance to HAs (e.g., erythromycin and Triton X-100) but only a twofold increase in resistance to penicillin. When subsequent mutations in penA and porIB were introduced from strain FA6140 into strain WV30 (FA19 mtrR) by transformation, resistance to penicillin increased incrementally up to a MIC of 1.0 μg/ml. Insertional inactivation of the gene (mtrD) encoding the membrane transporter component of the Mtr efflux pump in these transformant strains and in strain FA6140 decreased the MIC of penicillin by 16-fold. Genetic analyses revealed that mtrR mutations, such as the single base pair deletion in its promoter, are needed for phenotypic expression of penicillin and tetracycline resistance afforded by the penB mutation. As penB represents amino acid substitutions within the third loop of the outer membrane PorIB protein that modulate entry of penicillin and tetracycline, the results presented herein suggest that PorIB and the MtrC-MtrD-MtrE efflux pump act synergistically to confer resistance to these antibiotics.

Dinucleotide microsatellites from Eucalyptus sieberi: inheritance, diversity, and improved scoring of single-base differences

Genome ◽  
2001 ◽  
Vol 44 (6) ◽  
pp. 1041-1045 ◽  
Author(s):  
J C Glaubitz ◽  
L C Emebiri ◽  
G F Moran
Keyword(s):  
Base Pair ◽  
Mendelian Inheritance ◽  
Null Alleles ◽  
Fixation Index ◽  
Eucalyptus Nitens ◽  
Internal Reference ◽  
Single Base ◽  
Hardy Weinberg Equilibrium ◽  
Single Base Pair ◽  
Flanking Regions

Eight dinucleotide microsatellites were developed in Eucalyptus sieberi L. Johnson (silvertop ash), a member of the subgenus Eucalyptus. Transfer of six of these to the subgenus Symphyomyrtus and their Mendelian inheritance are demonstrated using a full-sib cross in Eucalyptus nitens. Genetic diversity parameters are presented for the eight loci based on a sample of 100 old-growth E. sieberi trees from a single natural stand. One locus, Es266, had an atypically high fixation index, and significantly deviated from Hardy-Weinberg equilibrium genotypic proportions, indicating the likely presence of null alleles. Two of the loci, Es076 and Es140, had many alleles that differed in size by only a single base pair, possibly because of short poly(A) or poly(T) stretches in their flanking regions. These two loci were by far the most polymorphic, but were difficult to score reliably on a capillary DNA sequencer. Reliability of scoring of these two one-base microsatellite loci was markedly improved by the incorporation of internal reference alleles into each sample analysed.Key words: SSRs, single base pair alleles, null alleles, internal reference alleles.

scholarly journals ISWI Remodelers Slide Nucleosomes with Coordinated Multi-Base-Pair Entry Steps and Single-Base-Pair Exit Steps

Cell ◽  
2013 ◽  
Vol 152 (3) ◽  
pp. 442-452 ◽  
Author(s):  
Sebastian Deindl ◽  
William L. Hwang ◽  
Swetansu K. Hota ◽  
Timothy R. Blosser ◽  
Punit Prasad ◽  
...  
Keyword(s):  
Base Pair ◽  
Single Base ◽  
Single Base Pair
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