Genetics partial blocks

The metabolic lesions that appear in human porphyrias represent only partial blocks. These metabolic lesions in general are inheritable. Several explanations may be suggested to explain these partial blocks genetically. It may be that a gene belonging to the biosynthetic chain of heme is altered qualitatively so that less enzyme is formed or the enzyme which is formed is less active or less stable. An alternative explanation is that enzyme formation or enzymic action of any particular step in the heme chain may be inhibited or controlled by substances produced by other biosynthetic chains which have their own specific genes on such a basis the defect would lie not in the biosynthetic chain of heme but in some other biosynthetic chain. Besides the genetic aspects, additional factors must be involved, since symptoms of certain porphyrias may appear only as late as middle age. 

An important feature in the mechanism of inheritance from the stand-point of our discussion lies in the existence of what have been inelegantly called "leaky genes" or less picturesquely "partial genetic blocks." Observation of a phenomenon of this sort was first made by Mitchell and Houlahanl in 1946 and was an outgrowth of the earlier pioneer studies on the genetics of Neurospora by Beadle and Tatum.2... 

From the standpoint of biochemical genetics and the genetotrophic principle, however, it seems likely that partial genetic blocks (which impose increased demands) may happen anywhere in the entire metabolic scheme in what may be assumed, without further evidence, to be in a random fashion. If this be the case, any and every nutritional need may be represented among those which are observed to be augmented. 

The SNAREs involved in the fusion of synaptic vesicles and of secretory granules in neuroendocrine cells, referred to as neuronal SNAREs, have been intensely studied and serve as a paradigm for all SNAREs. They include syntaxin 1A and SNAP-25 at the presynaptic membrane and synaptobrevin 2 (also referred to as VAMP 2) at the vesicle membrane. Their importance for synaptic neurotransmission is documented by the fact that the block in neurotransmitter release caused by botulinum and tetanus neurotoxins is due to proteolysis of the neuronal SNAREs (Schiavo et al. 2000). Genetic deletion of these SNAREs confirmed their essential role in the last steps of neurotransmitter release. Intriguingly, analysis of chromaffin cells from KO mice lacking synaptobrevin or SNAP-25 showed that these proteins can be at least partially substituted by SNAP-23 and cellubrevin, respectively (Sorensen et al. 2003 Borisovska et al. 2005), i.e., the corresponding SNAREs involved in constitutive exocytosis. 

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