Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure-labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C-terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle's loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest.
- MeSH
- alfa-galaktosidasa terapeutické užití MeSH
- biologické markery metabolismus MeSH
- dospělí MeSH
- Fabryho nemoc farmakoterapie metabolismus patologie MeSH
- ledvinové kanálky metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mucin 1 metabolismus MeSH
- mukoproteiny metabolismus moč MeSH
- nemoci ledvin etiologie metabolismus patologie MeSH
- posttranslační úpravy proteinů * MeSH
- sekvence aminokyselin MeSH
- trihexosylceramidy metabolismus MeSH
- uromodulin MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alfa-galaktosidasa MeSH
- biologické markery MeSH
- globotriaosylceramide MeSH Prohlížeč
- MUC1 protein, human MeSH Prohlížeč
- mucin 1 MeSH
- mukoproteiny MeSH
- trihexosylceramidy MeSH
- UMOD protein, human MeSH Prohlížeč
- uromodulin MeSH
- MeSH
- cerebrosidsulfatasa genetika MeSH
- lidé MeSH
- metachromatická leukodystrofie genetika MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- nesmyslný kodon MeSH
- substituce aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cerebrosidsulfatasa MeSH
- nesmyslný kodon MeSH
- MeSH
- cerebrosidsulfatasa genetika MeSH
- lidé MeSH
- metachromatická leukodystrofie genetika MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- nesmyslný kodon MeSH
- substituce aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cerebrosidsulfatasa MeSH
- nesmyslný kodon MeSH
- MeSH
- cerebrosidsulfatasa genetika MeSH
- lidé MeSH
- metachromatická leukodystrofie genetika MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- nesmyslný kodon MeSH
- substituce aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cerebrosidsulfatasa MeSH
- nesmyslný kodon MeSH
- MeSH
- cerebrosidsulfatasa genetika MeSH
- lidé MeSH
- metachromatická leukodystrofie genetika MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- nesmyslný kodon MeSH
- substituce aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cerebrosidsulfatasa MeSH
- nesmyslný kodon MeSH
An infant presented with multifocal myoclonus and cyanotic hypoxemia immediately after birth, and severe feeding problems, a protein-losing enteropathy, massive ascites and grand-mal epilepsy marked his rapid downhill course, with death at 17 weeks. At 2 weeks, brain MRI revealed grey matter heterotopias in the parieto-occipital regions suggestive of a cortical morphogenetic disorder. In cultured skin fibroblasts, lipid storage and reduced activities of ceramidase, galactosylceramide beta-galactosidase and glucosylceramide beta-glucosidase were evident. Autopsy disclosed generalised lysosomal lipid storage with macrophages and adrenal cortex prominently affected. The pattern of stored lipids in cultured fibroblasts and in dewaxed spleen tissue blocks was compatible with a diagnosis of prosaposin (pSap) deficiency (pSap-d). Neuropathologically, there was a pronounced generalised neurolysosomal storage combined with a severe depletion of cortical neurons and extreme paucity of myelin and oligodendroglia. This pathology, in particular the massive neuronal loss, differed from that in other neurolipidoses and could be explained by the reduced hydrolysis of multiple sphingolipids and the loss of pSap's neurotrophic function. The absence of immunostainable saposins on tissue sections and the presence of a homozygous c.1 A > T mutation in the prosaposin gene confirmed the diagnosis. PSap-d may be an underdiagnosed condition in infants with severe neurological and dystrophic signs starting immediately after birth.
- MeSH
- fatální výsledek MeSH
- fibroblasty metabolismus patologie MeSH
- glykolipidy metabolismus MeSH
- hydrolasy metabolismus MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- novorozenec MeSH
- saposiny nedostatek genetika MeSH
- sfingolipidy metabolismus MeSH
- vrozené poruchy metabolismu tuků genetika metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glykolipidy MeSH
- hydrolasy MeSH
- PSAP protein, human MeSH Prohlížeč
- saposiny MeSH
- sfingolipidy MeSH
A fatal infantile storage disorder with hepatosplenomegaly and severe neurological disease is described. Sphingolipids, including monohexosylceramides (mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), globotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide, were stored in the tissues. In general, cholesterol and sphingomyelin levels were unaltered. The storage process was generalized and affected a number of cell types, with histiocytes, which infiltrated a number of visceral organs and the brain, especially involved. The ultrastructure of the storage lysosomes was membranous with oligolamellar, mainly vesicular, profiles. Infrequently, there were Gaucher-like lysosomes in histiocytes. The neuropathology was severe and featured neuronal storage and loss with a massive depopulation of cortical neurons and pronounced fibrillary astrocytosis. There was a paucity of myelin and stainable axons in the white matter with signs of active demyelination. Immunohistochemical investigations indicated that saposins A, B, C and D were all deficient. The patient was homozygous for a 1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene which leads to a frameshift and premature stop codon. In the heterozygous parents, mutant cDNA was detected by amplification refractory mutation analysis in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA, indicating that the mutant mRNA was rapidly degraded. The storage process in the proband resembled that of a published case from an unrelated family. Saposins were also deficient in this case, leading to its reclassification as prosaposin deficiency, and her mother was found to be a carrier for the same c.803delG mutation. Both of the investigated families came from the same district of eastern Slovakia.
- MeSH
- CD antigeny * MeSH
- DNA primery chemie MeSH
- fibroblasty metabolismus MeSH
- gangliosidy metabolismus MeSH
- glykolipidy metabolismus MeSH
- glykoproteiny nedostatek genetika MeSH
- glykosfingolipidy metabolismus MeSH
- kodon MeSH
- laktosylceramidy biosyntéza MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutace * MeSH
- novorozenec MeSH
- polymerázová řetězová reakce MeSH
- saposiny MeSH
- sekvence nukleotidů MeSH
- sfingolipidózy genetika metabolismus patologie MeSH
- sulfoglykosfingolipidy metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- CD antigeny * MeSH
- CDw17 antigen MeSH Prohlížeč
- DNA primery MeSH
- gangliosidy MeSH
- glykolipidy MeSH
- glykoproteiny MeSH
- glykosfingolipidy MeSH
- kodon MeSH
- laktosylceramidy MeSH
- PSAP protein, human MeSH Prohlížeč
- saposiny MeSH
- sulfoglykosfingolipidy MeSH
A fast and simple method for determination of sulfatides in the urine of patients with metachromatic leukodystrophy (MLD, arylsulfatase A deficiency) has been developed. The procedure consists of two steps: extraction of total urinary lipids by reversed-phase chromatography and their HPTLC separation. Two types of sorbents based on different matrixes were compared, of which the hydroxyethyl methacrylate C-18 type sorbent was found to be superior. Twenty-milliliter aliquots of urine are sufficient for the analysis. The technique is appropriate for simultaneous qualitative identification and semiquantitative densitometric determination and is suitable for routine work. The amount of sulfatides is expressed in relation to sphingomyelin, which copurifies with sulfatides and better reflects the level of membrane lipids in urine than commonly used parameters (creatinine, urine volume, etc.). The ranges were found to be 0.15-0.68 nmol sulfatide/nmol sphingomyelin for control individuals and 3.5-27.2 nmol sulfatide/nmol sphingomyelin for MLD patients. The excretion of sulfatides is pathonognomic for true MLD (due to the accumulation in kidney) and therefore its analysis is important for evaluation of suspected MLD cases including clinically and enzymatically atypical cases. The method is also useful as a complementary analysis for other lipidoses with high excretion of sphingolipids in urine (e.g., Fabry disease).
- MeSH
- chromatografie na tenké vrstvě metody MeSH
- chromatografie metody MeSH
- Fabryho nemoc moč MeSH
- lidé MeSH
- lipidy moč MeSH
- metachromatická leukodystrofie diagnóza moč MeSH
- proteinurie moč MeSH
- studie případů a kontrol MeSH
- sulfoglykosfingolipidy moč MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- lipidy MeSH
- sulfoglykosfingolipidy MeSH
