Splicing mRNA, alternative modes

Alternative Modes of mRNA Splicing Present a Potent Mechanism for Posttranscriptional Regulation Gene Expression Is Also Regulated at the Levels of Translation and Polypeptide Processing Patterns of Regulation Associated with Developmental Processes... 

Alternative Modes of mRNA Splicing Pr esent a Potent Mechanism for Posttranscriptional Regulation... 

Eukaryotes potentially have many more opportunities for control of gene expression than do bacteria. For example, the cell could take advantage of control at the level of the processing of primary transcripts. It is known that RNA is not transported across the nuclear membrane until all introns are excised. A more subtle form of control could involve alternative modes of splicing a particular transcript. There are now examples known where this occurs to yield different mRNA molecules. Perhaps one of the best-known examples of yet another level of control in eukaryotes is that of translational control of globin synthesis. 

The 13-residue neurotensin was firsf isolafed from the hypothalamus but is more abundant in cells of the ileum. It induces gut contraction, lowers blood pressure, and has a variety of ofher effecfs. Substance P (SP Table 30-4) has been regarded as a possible neurotransmitter for some time but is also foimd in the digestive tract. It is the most abundant of a family of five neurokinins (or tachykinins). Others include neurokinin A (substance K), neurokinin B, neuropeptide K, and neuropeptide y. They have a common C-terminal sequence FXGLM-NH2. ° Substance P is thought to be involved in the perception of pain, and mice lacking a substance P receptor appear to have reduced sensitivity to pain. Substance P as well as the related substance K are derived from two large precursor proteins, which appear to arise as a result of alternative modes of splicing of mRNA.29... 

The mode of inheritance of EPP is complex but has recently been clarified by enzymatic and molecular studies of families. Molecular analysis has identified more than 60 disabling mutations of the FECH gene that are inherited in EPP families in an autosomal dominant pattern. Within these families, FECH activities in patients with overt disease are lower than the half-normal activities in their asymptomatic relatives with the same mutation. Thus a decrease in FECH activity to less than 50% of normal appears to be essential for development of sufficient overproduction of protoporphyrin to produce symptoms. In most families, this further decrease is produced by inheritance of a low expression FECH allele trans to the severe mutation. The low expression allele is a polymorphic FECH variant present in about 10% of the Western European population. Substitution of a T nucleotide by a C nucleotide at a polymorphic site in intron 3 (IVS3-48C/T) enhances use of an alternative splice site, leading to increased formation of an unstable, untranslated mRNA and reduction of FECH expression by about 25%. This pattern of inheritance has been described as autosomal dominant with modulation by expression of the wild type of FECH allele. Uncommon autosomal recessive cases of EPP have also been reported. ... 

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