ineffective renal tissue perfusion
Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system CNS. On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined ineffective renal tissue perfusion astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.
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Some studies, however, indicate that its incidence is much higher than reported, particularly in some regions of Southern Italy, some parts of Cuba, and Tunisia, as well as in some populations of Mexican-Indian origin in Arizona and Colorado of the United States Ben Turkia et al. On the basis of the clinical course, fucosidosis ineffective renal tissue perfusion been divided into a severe infantile fast-progressing form type 1 and a milder form type 2although the disease often presents with a continuum of an entire set of clinical features.
Fucosidosis is dominated by neurological symptoms like progressive mental and motor deterioration, and seizures, but it is often accompanied by coarse facial features, growth retardation, dysostosis multiplex, angiokeratoma, visceromegaly and a broad range of further symptoms. Half of the affected fenal die before 10 years of age Willems et al.
So far, at least 29 different mutations in the FUCA1 gene on chromosome 1p34 of fucosidosis individuals have been identified, most of them in homozygous form due to high consanguinity Malm et al. Like many other LSDs, fucosidosis lacks a clear genotype-phenotype relationship, and the same homozygous FUCA1 mutation can lead to either the type-1 or the type-2 phenotype Willems et al.
Thus, a considerable number of more than 20 fucosylated substrates are click to accumulate in great amounts in various tissues which, as a consequence, are also excreted in the urine of affected individuals Michalski and Klein, Beside oligosaccharides and glycolipids, which are common storage products of glycoproteinoses, the vast majority of storage material comprises fucosylated glycoproteins and glycoasparagines Strecker et al.
These compounds are exclusively ineffective renal tissue perfusion in fucosidosis and hence can be used as diagnostic biomarkers.
Chronic Renal Failure CRF NCLEX Review Care Plans
In liver, brain, pancreas and skin of fucosidosis individuals, severely affected cell types often show extensive vacuolation with a foam-cell-like appearance. Although most cell types show empty vacuoles, indicating storage of water soluble material, the vacuoles in some cell types also include granular or lamellar electron-dense structures, as detected by electron microscopy, indicating more heterogeneous storage material than is known from ineffective renal tissue perfusion LSDs Willems et al. To date, no general treatment for fucosidosis is available.
Very few individuals have been successfully treated with bone marrow transplantation BMT but there has been at least some neurological improvement in some cases Krivit et al.
INTRODUCTION
A dog model in English Springer spaniels was characterized a long time ago, which closely resembles the human disease Abraham read article al. Moreover, a domestic shorthair cat model lacking fucosidase activity has been reported, and shows cerebellar dysfunction and storage pathology Arrol et al. In this study, we establish a knockout mouse model for fucosidosis by using a gene replacement strategy and demonstrate that this mouse model is an easy to manage model system in order to understand the mechanisms of disease progression, to identify putative biomarkers for reliable diagnosis and to address therapeutic strategies such as Ineffective renal tissue perfusion.
Correct homologous recombination of the gene-targeting construct was confirmed by performing PCR amplification with genomic DNA, resulting in a 4. S1Bupper paneland subsequent sequencing of the PCR products.
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Routine genotyping was performed with a multiplex PCR using an nptI-specific primer for detection of the knockout allele and a primer that bound to exon 1 for detection of the wild-type allele Fig. S1Blower panel. Transcriptional inactivation of Fuca1 was initially validated in several tissues by performing quantitative real-time PCR qPCRand revealed some residual Fuca1 mRNA in ineffective renal tissue perfusion and brain but not in liver and kidney Fig.
View large Download slide Fuca1 deficiency validation and expression of lysosomal enzymes. The different molecular weights of Lamp1 just click for source attributed to organ-specific glycosylation. Taken together, these results on genomic, transcript and enzyme levels unambiguously confirm Fuca1 deficiency of our mouse model and suggest that it can be used as a reliable fucosidosis animal model.
Regulation of other lysosomal hydrolases involved in glycoprotein degradation We next determined ineffective renal tissue perfusion levels and enzymatic activities of several other lysosomal hydrolases, which are involved in glycoprotein degradation, as well as the expression level of the lysosomal membrane protein Lamp1. Western blot analysis revealed that there was a twofold increase in the amount of the lysosomal hydrolase cathepsin D in cerebrum and kidney of Fuca1-deficient mice Fig. Lamp1 expression was upregulated in cerebrum at the transcript and protein levels, as demonstrated by qPCR analyses Fig.]
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