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摘要
Various transgenic mouse models for human defects in pterin and biogenic amine metabolism are available today, including PAH, TH, D beta H, and MAO-A. The only exception is the gene encoding AADC. For the TPH1, TPH2, PMNT and COMT genes, knockout mice were generated yielding in all cases no phenotypes or only minor changes in corresponding metabolite levels. For the comparable human genes only single nucleotide polymorphisms (SNPs) were reported and no clear genetic association with a distinct clinic entity was identified. Regarding the so-called secondary disorders of neurotransmitter metabolism, mouse models were generated for defects in tetrahydrobiopterin (BH(4)) metabolism, i.e. DRD, PTPS, SR, PCD and DHPR, as well as for Lesch-Nyhan syndrome and Menkes disease. No animal models are available for the autosomal recessive form of GTPCH deficiency, despite great efforts of various groups to generate a knockout mouse variant (unpublished results and personal communication to BT/RHF). A long list of knockout animals have been generated that interfere with functions in release, clearance, transport, or receptor signaling in the monoamine neurotransmitter system, including tryptophan hydroxylase deficiency, yet again no corresponding human disorders could be assigned. Inactivation of the genes encoding for critical enzymes in folate metabolism (Mthfr, Shmt1, Mthfd1, Mthfd2, Mtrr, Mtr) and transport (Folr1, 2, 3, Pcft and RFC1) have provided limited insight into the causal pathways for folate-associated pathologies such as colon cancer and selected congenital malformations. Selected SNPs in these genes have been identified in humans, several of which have been found to be risk factors for neural tube and conotruncal heart defects.
Four major international mouse knockout programs are currently funded, and it is now only a matter of time before mouse mutants for all genes coding for neurometabolic enzymes or proteins will be made available to the research community. However, not every genetically modified mouse model bears the same potential usefulness, as most often the gene targeted and even the gene-trapped models result in complete inactivation of the gene product, whereas genetic variations in humans often are not null mutations but rather single-nucleotide alterations, resulting in a modest decrease in functionality. Moreover, regarding phenotypical variations within individual disease states, effects of protein modifiers and the genetic background have to be considered. Studies in genetically modified mice are almost exclusively conducted in inbred strains with a constant or specific genetic background, which is in stark contrast to human patients that are invariably genetically heterogeneous. Another level of complexity or challenge for the modeling of human disorders lies in behavioral characterization of mice, for example ptosis, depression, ADHD, and schizophrenia. While methodologies for such analyses are improving, the relevance of corresponding testing to human disorders remains controversial. Finally, reference values and availability of specimens or samples for diagnosis are not always comparable between mice and humans. An example would be CSF, which is commonly evaluated in human disease states but given their small size, it is difficult to obtain from mice and is rarely be collected or analyzed.
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- 出版日期2009-12
