Splicing mutations affecting

O Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33(4) 497-501... 

Mutations in splice sites affect the accuracy of intron removal from hnRNA during posttran-scriptionai processing. As illustrated in Figure 1-4-4, if a splice site is lost through mutation, spliceosomes may ... 

Pyruvate Idnase deficiency (OMIM 266200) is the most common cause of nonspherocytic hemolytic anemia due to defective glycolysis. The allelic frequency is estimated to be around 2%. The consequent lack of sufficient energy, which is required for normal functioning and cellular survival, shortens the life span of the mature PK-deficient erythrocyte. Consequently, PK-deficient patients display a phenotype of nonspherocytic hemolytic anemia albeit with variable clinical severity. The clinical symptoms vary from neonatal death to a well-compensated hemolytic anemia. Patients benefit in general from a splenectomy. Pyruvate kinase deficiency is transmitted as an autosomal recessive disease. To date, more than 130 mutations in PKLR have been reported to be associated with pyruvate kinase deficiency (see Figure 21-10 for overview see reference 221). Most (70%) of these mutations are missense mutations affecting conserved residues in structurally and functionally important domains of PK. Splice site mutations, a deletion. 

Fig. 2 Schematic representation of the V2 receptor and identification of 193 putative disease-causing AVPR2 mutations. Predicted amino acids are shown as the one-letter amino acid code. A solid symbol indicates a codon with a missense or nonsense mutation a number indicates more than one mutation in the same codon other types of mutations are not indicated on the figure. There are 95 missense, 18 nonsense, 46 frameshift deletion or insertion, 7 inframe deletion or insertion, 4 splice-site, and 22 large deletion mutations, and 1 complex mutation. The gain-of-function mutations affecting codons R137 and F229 are indicated...

In the history of drug metabolism, prominent were the discoveries of genetic variability of the metabolism of debrisoquine (14) and of sparteine (15). Subsequent studies indicated that both drugs are metabolized by the same enzyme (16), which turned out to be the P450 cytochrome CYP2D6 (17). The enzyme s variations were found to be complex (18) enzyme activity could be absent because of frameshift mutations, splicing defects, gene deletion, or the presence of a stop codon. The enzyme may function slowly because of various kinds of mutation, whereby some mutations affected only the interaction with specific substrates. Enzyme duplication or multiplication could lead to very fast action. 

P-Thalassemla (MIM 141900) A very wide variety of mutations in the p-globin gene, including deletions, nonsense and frameshift mutations, and others affecting every aspect of its structure (eg, splice sites, promoter mutants)... 

The distribution of open channel times is mainly determined by the rate constants S and K (2 is assumed to be very small). Mutations which change the C to O transition (e.g., the burst size of channel opening) have not been characterized yet. However, structural alterations which affect k and thereby the level of steady state inactivation have been described for Sh channels [29,60]. Different splice variants of Sh channels... 

Answer D. At the 3 border of exon 2 with intron 2, a splice donor site is present. A mutation could cause exon skipping. Choices A, B, and C would not affect transcription or mRNA processing. 

The biochemical basis for the trait is an almost complete absence of one form of cytochrome P-450, CYP2D6. It seems that there are several mutations, which give rise to the poor metabolizer phenotype. These mutations produce incorrectly spliced, variant mRNAs in the liver from poor metabolizers. At least three mutant alleles have been described for the CYP2D6 gene and in those with "poor metabolizer" status. A large number of mutations have also been described some of which, but not all, affect enzyme activity. However, for some of... 

Factor IX (Christmas factor) is next in the intrinsic mechanism cascade. It can be activated either by XIa or by Vila of the tissue factor pathway. The absence of a functional factor IX leads to the inherited X-linked bleeding disorder hemophilia B which affects 1 in 30,000 males. The condition can be mild or very serious551552 and may be caused by a variety of mutations or by incorrect splicing of the messenger RNA for the 416-residue factor IX. The level of factor IX in blood increases with age, almost doubling by old age.552a... 

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