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.

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.

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

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

Six Different Point Mutations in Seven Danish Families with Symptomatic Protein C Deficiency

1995 ◽  
Vol 73 (02) ◽  
pp. 186-193 ◽  
Author(s):  
Bent Lind ◽  
Marianne Schwartz ◽  
Sixtus Thorsen
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Family Members ◽  
Point Mutations ◽  
Patient Specific ◽  
Missense Mutations ◽  
Coding Region ◽  
Protein C Deficiency ◽  
Epidermal Growth Factor Domain ◽  
Increased Risk

SummarySix different point mutations of the protein C gene are described in seven Danish families with protein C deficiency associated with an increased risk of venous thromboembolism. All affected family members are heterozygotes for the mutated protein C genotype. One mutation is a G2992→A transition at position +5 in the 5’ splice site of intron D. The other five mutations affect the protein coding region. One is a Cl432→T transition in exon III converting the highly conserved Arg15 to Trp in the Gla-domain. Another mutation is a G3157→C transversion in exon V converting the non-conserved Gly72 to Arg in the epidermal growth factor domain. The remaining three mutations are located in non-conserved amino acid positions in exon IX and affect the serine proteinase domain. The first is a G8559→C transversion converting Gly282 to Arg. The second is a C8571→T transition (present in two families) converting Arg286 to Cys. The third is a C8695→T transition converting Pro327 to Leu. In each family the protein C deficiency cosegregates or probably cosegregates (one family, G8559→C) with the mutation. All affected family members exhibit a reduction of both the antigen and the functional plasma concentration of protein C to approximately 50% of normal indicating that the mutated protein C is not present (type 1 deficiency) or only present in low amounts in plasma. Agarose gel electrophoresis followed by Western blotting shows that the Arg15→Trp substitution is associated with a normal as well as an abnormal migrating plasma protein C band. This provides positive evidence for that both the normal and mutated alleles are expressed (type 2 deficiency). The five other mutations are associated with only one band with the mobility of normal protein C. In one family a novel G1390→A transition converting the normal Ala1 to Thr was demonstrated. This mutation is not linked to the patient specific G8559→C transversion. In conclusion one splice site mutation and five different missense mutations of the protein C gene are described.

A novel splice site mutation (3157+1G>T) in the dystrophin gene causing total exon skipping and DMD phenotype

2001 ◽  
Vol 17 (3) ◽  
pp. 239-239 ◽  
Author(s):  
M. Sironi ◽  
S. Corti ◽  
F. Locatelli ◽  
R. Cagliani ◽  
G.P. Comi
Keyword(s):  
Splice Site ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Dystrophin Gene ◽  
Site Mutation

Erratum: A novel splice site mutation (3157+1G>T) in the dystrophin gene causing total exon skipping and DMD phenotype

2001 ◽  
Vol 18 (6) ◽  
pp. 552-552
Author(s):  
M. Sironi ◽  
S. Corti ◽  
F. Locatelli ◽  
R. Cagliani ◽  
G.P. Comi
Keyword(s):  
Splice Site ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Dystrophin Gene ◽  
Site Mutation

Poor Relationship between Phenotypes of Protein S Deficiency and Mutations in the Protein S Alpha Gene

1999 ◽  
Vol 82 (12) ◽  
pp. 1634-1638 ◽  
Author(s):  
José Hermida ◽  
Pier Mannuccio Mannucci ◽  
Elena Faioni
Keyword(s):  
Splice Site ◽  
Genetic Defect ◽  
Splice Site Mutation ◽  
Protein S ◽  
Nucleotide Sequencing ◽  
Type I ◽  
Protein S Deficiency ◽  
Site Mutation ◽  
Single Strand Conformational Polymorphism ◽  
S Deficiency

SummaryBy single strand conformational polymorphism, nucleotide sequencing and enzyme restriction, we analyzed the protein S α gene in 17 protein S-deficient probands and in their available family members. The relationship between genotype and phenotype was also evaluated. Twelve different sequence variations were identified in 17 probands. Ten were putative causal mutations distributed in 16 probands: 4 were nonsense, 5 missense and one a splice site mutation. In most families in which a mutation was identified, more than one phenotype of PS deficiency was present. The same splice site mutation (intron j G-A, exon 10+5) was associated with type I deficiency in one family and with type I/III in another unrelated family. A phenotypic discrepancy was also observed for the Arg474Pro, Gly597Asp and Arg410stop mutations. Glu26Ala, previously reported in kindreds with type I deficiencies, was found in association with I, II and III phenotypes in four unrelated kindreds. Phenotypic analysis of protein S deficiency is poorly related to the underlying genetic defect.

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