Acceptor splice site mutation in the invariant AG of intron 5 of the protein C gene, causing type I protein C deficiency

1993 ◽  
Vol 92 (5) ◽  
pp. 506-508 ◽  
Author(s):  
Jos� Manuel Soria ◽  
Jordi Fontcuberta ◽  
Miguel Chill�n ◽  
Montserrat Borrell ◽  
Xavier Estivill ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Splice Site Mutation ◽  
Type I ◽  
Site Mutation ◽  
Protein C Deficiency ◽  
Acceptor Splice Site

scholarly journals Splice site mutation in the human protein C gene associated with venous thrombosis: demonstration of exon skipping by ectopic transcript analysis

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2423-2432
Author(s):  
B Lind ◽  
WW van Solinge ◽  
M Schwartz ◽  
S Thorsen
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Family Members ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Peripheral Blood Lymphocytes ◽  
Nucleotide Sequencing ◽  
Liver Protein ◽  
Site Mutation ◽  
Protein C Deficiency

Heterozygosity for a G-->C mutation converting the highly conserved Gln184 (CAG) to His (CAC) was identified at the last nucleotide of exon 7 of the protein C gene in two family members with deep vein thrombosis. As the nucleotide is a part of the 5 splice site of intron G, it was examined how the mutation affected splicing of protein C pre- mRNA. Relevant protein C cDNA fragments were amplified with polymerase chain reaction after reverse transcription of ectopic mRNA from peripheral blood lymphocytes. Southern blot analysis and nucleotide sequencing of these fragments showed a fragment (A) corresponding to correctly spliced mRNA originating from the normal allele and a fragment (B) corresponding to a truncated mRNA lacking exon 7, originating from the mutant allele. A third fragment (C) lacking exons 7 and 8 was identified in both affected and unaffected family members, as well as in normal controls. Analysis of human liver protein C mRNA indicated that the ectopic lymphocyte mRNA was qualitatively representative for the tissue-specific mRNA. In conclusion, evidence is provided showing that the mutation abolishes formation of correctly spliced mRNA. This agrees with the observation that the mutation results in a type 1 protein C deficiency.

Molecular characterization of novel splice site mutation causing protein C deficiency

2016 ◽  
Vol 27 (5) ◽  
pp. 585-588 ◽  
Author(s):  
Mohamed H. Al-Hamed ◽  
Fatma AlBatniji ◽  
Ghadah A. AlDakheel ◽  
Huda El-Faraidi ◽  
Azzah Al-Zahrani ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Splice Site ◽  
Protein C ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Protein C Deficiency

scholarly journals Splice site mutation in the human protein C gene associated with venous thrombosis: demonstration of exon skipping by ectopic transcript analysis

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2423-2432 ◽  
Author(s):  
B Lind ◽  
WW van Solinge ◽  
M Schwartz ◽  
S Thorsen
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Family Members ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Peripheral Blood Lymphocytes ◽  
Nucleotide Sequencing ◽  
Liver Protein ◽  
Site Mutation ◽  
Protein C Deficiency

Abstract Heterozygosity for a G-->C mutation converting the highly conserved Gln184 (CAG) to His (CAC) was identified at the last nucleotide of exon 7 of the protein C gene in two family members with deep vein thrombosis. As the nucleotide is a part of the 5 splice site of intron G, it was examined how the mutation affected splicing of protein C pre- mRNA. Relevant protein C cDNA fragments were amplified with polymerase chain reaction after reverse transcription of ectopic mRNA from peripheral blood lymphocytes. Southern blot analysis and nucleotide sequencing of these fragments showed a fragment (A) corresponding to correctly spliced mRNA originating from the normal allele and a fragment (B) corresponding to a truncated mRNA lacking exon 7, originating from the mutant allele. A third fragment (C) lacking exons 7 and 8 was identified in both affected and unaffected family members, as well as in normal controls. Analysis of human liver protein C mRNA indicated that the ectopic lymphocyte mRNA was qualitatively representative for the tissue-specific mRNA. In conclusion, evidence is provided showing that the mutation abolishes formation of correctly spliced mRNA. This agrees with the observation that the mutation results in a type 1 protein C deficiency.

Ectopic Transcript Analysis Indicates that Allelic Exclusion is an Important Cause of Type I Protein C Deficiency in Patients with Nonsense and Frameshift Mutations in the PROC Gene

1996 ◽  
Vol 75 (06) ◽  
pp. 870-876 ◽  
Author(s):  
José Manuel Soria ◽  
Lutz-Peter Berg ◽  
Jordi Fontcuberta ◽  
Vijay V Kakkar ◽  
Xavier Estivill ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Allelic Exclusion ◽  
Polymorphism Analysis ◽  
Type I ◽  
Protein C Deficiency ◽  
Nonsense Mutations ◽  
Stop Codons

SummaryNonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons

scholarly journals A splice site mutation of alpha-spectrin gene causing skipping of exon 18 in hereditary elliptocytosis

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2791-2798 ◽  
Author(s):  
N Alloisio ◽  
R Wilmotte ◽  
J Marechal ◽  
P Texier ◽  
L Denoroy ◽  
...  
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Low Grade ◽  
Site Mutation ◽  
Acceptor Splice Site ◽  
Genetic Lesion ◽  
Major Disadvantage ◽  
Internal Position ◽  
Alpha Spectrin ◽  
Self Association

Abstract Spectrin Oran (alpha II/21) has been reported previously as a variant of the alpha II domain. Its expression level is low (10% of total spectrin) in heterozygotes denoting a major disadvantage of the mutated alpha-chain dimer or tetramer with respect to their normal counterparts. Spectrin Oran is associated with symptomatic elliptocytosis in the homozygous state. A 1-minute digestion time allowed to perceive a fast trypsin cleavage (not existing normally) after Arg 890 (helix 3 of repeating segment alpha 9). The responsible change was the lack of amino acids 822 to 862 (helix 2 of repeating segment alpha 8). Such a situation fits with the phasing of spectrin according to which mutated helix 2 and distorted helix 3 are adjacent to one another. The internal position of the structural change accounts for the slight self-association defect. The ultimate genetic lesion was a G to A substitution (intronic position-1) in the acceptor splice site of intron 17 resulting in skipping of exon 18. The substitution also created an acceptor splice site 1 base downstream, but the latter was used at a low grade.

An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema

1991 ◽  
Vol 88 (2) ◽  
Author(s):  
Z. Siddique ◽  
A.R. McPhaden ◽  
D.F. Lappin ◽  
K. Whaley
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Type I ◽  
C1 Inhibitor ◽  
Site Mutation ◽  
Inhibitor Gene
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