Neurological Implications of the Genetic Mouse Models for Human Phenylketonuria and Hyperphenylalaninemia

McDonald, J. David

doi:10.1007/978-1-4615-4887-4_12

Cited by 8 publications

(11 citation statements)

References 57 publications

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“…We recently showed that the Pah enu1 mouse is a model for BH 4responsive PAH deficiency (Gersting et al 2010). Pah enu1 was generated by germline mutagenesis, carries a mutation leading to a V106A amino acid substitution in the regulatory domain, and shows a mild hyperphenylalaninemia phenotype (McDonald et al 1990;Scavelli et al 2005;Shedlovsky et al 1993;Thöny et al 2004). We demonstrated that loss of function in this animal results from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme.…”

Section: Bh 4 : From a Natural Enzyme Cofactor To A Pharmacological Cmentioning

confidence: 86%

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

Muntau¹,

Gersting²

2010

J of Inher Metab Disea

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The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life.

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Section: Bh 4 : From a Natural Enzyme Cofactor To A Pharmacological Cmentioning

confidence: 86%

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

Muntau¹,

Gersting²

2010

J of Inher Metab Disea

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“…Bode et al (1988), then McDonald et al (1990 were the first to use ENU for the production of mouse mutations with effects on the metabolism of phenylalanine and resulting in phenylketonuria. Bode et al (1988), then McDonald et al (1990 were the first to use ENU for the production of mouse mutations with effects on the metabolism of phenylalanine and resulting in phenylketonuria.…”

Section: Genome-wide Induction Of New Mutant Allelesmentioning

confidence: 99%

Chemical mutagenesis of the mouse genome: an overview

Gu�net

2004

Genetica

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The careful comparison of the phenotypic variations generated by different alleles at a given locus, including of course, those alleles with a deleterious effect, is often an important source of information for the understanding of gene functions. In fact, every time it is possible to match a specific alteration observed at the genomic level with a particular pathology, it is possible to establish a relationship between a gene and its function. When considered from this point of view, the production of new mutations by experimental mutagenesis appears as an alternative to the strategy of in vitro gene invalidation by homologous recombination in embryonic stem (ES) cells, with the advantage that experimental mutagenesis does not require any previous knowledge of the gene structure at the molecular level. Homologous recombination in ES cells is a 'gene driven' approach, in which mutant alleles are produced for those genes that we already know. Experimental mutagenesis, on the contrary, is a 'phenotype driven' approach, in which unknown genes are identified based on phenotypic changes. Also, while homologous recombination in ES cells requires a rather sophisticated technology, mutagenesis is simple to achieve but relies greatly on the efficiency of the mutagenic treatment as well as on the use of an accurate protocol for phenotyping. In this review, we will address a few comments about the different techniques that can be used for the induction of point mutations in the mouse germ line with special emphasis on chemical mutagenesis. We will also discuss the limitations of experimental mutagenesis and the necessity to look for alternative ways for the discovery of new genes and gene functions in the mouse.

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“…The success of any mutation screen, therefore, is dependent on the forward mutation rate. Some mouse strains, such as BTBR/J, can tolerate a single high dose of ENU to achieve relatively high forward mutation rates (~1/250 per locus per gamete) (McDonald et al, 1990;Shedlovsky et al, 1993). Other strains, such as C57BL/6J, required multiple weekly injections of lower ENU doses to achieve a somewhat comparable forward mutation rate (~1/800 per locus per gamete) (Justice et al, 2000).…”

Section: Strain Choicementioning

confidence: 99%

Forward Genetic Screens to Identify Circadian Rhythm Mutants in Mice

Siepka¹,

Takahashi²

2005

Methods in Enzymology

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This article describes the methods and techniques used to produce mutagenized mice to conduct high-throughput forward genetic screens for circadian rhythm mutants in the mouse. In particular, we outline methods to safely prepare and administer the chemical mutagen N-nitrosoN-ethylurea (ENU) to mice. We also discuss the importance of selecting mouse strain and outline breeding strategies, logistics, and throughput to produce these mutant mice. Finally, we discuss the breeding strategies that we use to confirm mutation heritability.

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Neurological Implications of the Genetic Mouse Models for Human Phenylketonuria and Hyperphenylalaninemia

Cited by 8 publications

References 57 publications

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

Chemical mutagenesis of the mouse genome: an overview

Forward Genetic Screens to Identify Circadian Rhythm Mutants in Mice

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