Pku birth defect Video
Birth Defects and Prenatal Diagnosis - Embryology Anatomy Student Lecture - V-Learning™ pku birth defectGive to Save Lifetimes
It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase PAHwhich is necessary for conversion of Phe pku birth defect tyrosine Tyr. This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology.
Age and sex-matched heterozygous Pah-KO Het mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit.
These mice exhibit phenotypes that closely resemble Pku birth defect patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice.
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Altogether, biochemical, behavioral, and pathologic features pkk this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical pku birth defect and drug development. Subject terms: Diseases, Pathogenesis, Experimental models of disease, Preclinical research, Translational research Go to: Introduction Phenylketonuria PKU is an autosomal recessive inborn error of l-phenylalanine Phe metabolism.
It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase PAH activity, which is necessary for conversion pku birth defect Phe to tyrosine Tyrdue to mutations in the Pah gene 1 — 3. This metabolic error results in buildup of Phe and secondary metabolites and lower Tyr concentration in blood and in brain, which causes degenerative neuropathology and neurological symptoms and intellectual deficits 4 — 7.
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Once confirmed, all patients are clinically monitored and require a lifelong treatment to slow the development of neuropathology that is associated with PKU. Treatment is centered on dietary modification to include specially manufactured diet that is low in protein and Phe free. However, maintaining adequate adherence to such low-protein, low Phe diet is challenging.
Patients that do not adhere to the diet regimen or that are clinically non-diagnosed exhibit progressive development delay, characteristic poorly or non-pigmented skin and hair, mousy odor, neurological pku birth defect, cognitive deficits, and behavioral and social problems 10 Among various available mouse and rat models of PKU, Pahenu2 mice have been extensively used in preclinical assessment which has pku birth defect in better understanding of PKU disease biology. The Pahenu2 mouse model was generated via nitrosourea-induced chemical mutagenesis in the BTBR strain It has a FS missense mutation in the catalytic domain of mouse PAH protein 1314 that results in normal transcription of Pah mRNA but generation of an inactive PAH protein, which has negative effect on the wild-type protein subunits.
The active PAH enzyme works as a dimer and tetramer due to presence of C-terminal oligomerization domain; therefore, incorporation of the mutant full-length protein reduces activity of the enzyme complex. Hence the magnitude of correction when testing therapeutics that rely on production of active PAH enzyme is underestimated Moreover, degenerative neuropathology characterized by myelin disorder which is often observed in early and continuously treated PKU patients has not been consistently reported in this model The BTBR mice, background more info for Pahenu2, exhibit corpus callosum agenesis and hippocampal commissure defect which can impact behavior and assessment of brain pathology endpoints 17 Additionally, use of protein-based assays for assessment of efficacy or confirmation of mechanism of action for biotherapeutics such as Pah pku birth defect replacement or Pah mRNA in this model can be challenging as most of the analytical antibodies cross-react to both mouse and human PAH protein To provide an alternative PKU model with no endogenous PAH protein produced, pku birth defect generated a novel Pah knock-out KO mouse model by introducing a stop codon at the very beginning of the Pah codon 7 gene.
This is the first attempt at creating Pah-KO mouse model and as such prevents the production click mouse PAH protein and therefore eliminates any background PAH detection.]
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