AIMS: The reaction to diagnosis and quality of life (QOL) in autosomal dominant tubulointerstitial kidney disease (ADTKD) due to
- MeSH
- dospělí MeSH
- genetické testování MeSH
- kvalita života * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mucin 1 * genetika MeSH
- mutace * MeSH
- nemoci ledvin * genetika psychologie MeSH
- průřezové studie MeSH
- senioři MeSH
- uromodulin * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.
- MeSH
- alely MeSH
- anemie genetika MeSH
- biopsie MeSH
- chronická nemoc MeSH
- dánio pruhované embryologie genetika MeSH
- dítě MeSH
- dominantní geny MeSH
- dospělí MeSH
- endoplazmatické retikulum metabolismus MeSH
- exom genetika MeSH
- fenotyp MeSH
- Golgiho aparát metabolismus MeSH
- heterozygot * MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA analýza genetika MeSH
- missense mutace genetika MeSH
- mladý dospělý MeSH
- molekulární modely MeSH
- mutace * MeSH
- nemoci ledvin genetika patologie MeSH
- neutropenie genetika MeSH
- novorozenec MeSH
- progrese nemoci MeSH
- rodokmen MeSH
- růstová retardace plodu genetika MeSH
- sekvence aminokyselin MeSH
- senioři MeSH
- syndrom MeSH
- translokační kanály SEC chemie genetika MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
- MeSH
- cytosin metabolismus MeSH
- genetická vazba MeSH
- haplotypy MeSH
- lidé MeSH
- minisatelitní repetice * genetika MeSH
- mucin 1 * genetika metabolismus MeSH
- mutace * MeSH
- polycystické ledviny autozomálně dominantní * MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
BACKGROUND: The article describes the clinical, biochemical, enzymological and molecular genetics findings in two patients from two families with xanthinuria type I. METHODS: Biochemical analysis using high performance liquid chromatography, allopurinol loading test and analysis of xanthine oxidase activity in plasma and of uromodulin excretion in urine were performed. Sequencing analysis of the xanthine dehydrogenase gene and the haplotype and statistical analyses of consanguinity were performed. RESULTS: Probands showed extremely low concentrations of uric acid, on seven occasions under the limit of detection. The concentration of uric acid in 38-year-old female was 15 μmol/L in serum and 0.04 mmol/L in urine. Excretion of xanthine in urine was 170 mmol/mol creatinine. The concentration of uric acid in 25-year-old male was 0.03 mmol/L in urine. Excretion of xanthine in urine was 141 mmol/mol creatinine. The allopurinol loading test confirmed xanthinuria type I. The xanthine oxidase activities in patients were 0 and 0.4 pmol/h/mL of plasma. We found three nonsense changes: p.P214QfsX4 and unpublished p.R825X and p.R881X. CONCLUSIONS: We found two nonconsanguineous compound heterozygotes with xanthinuria type I caused by three nonsense changes. The methods used did not confirm consanguinity in the probands, thus there might be an unconfirmed biological relationship or mutational hotspot.
- MeSH
- DNA primery MeSH
- dospělí MeSH
- elektroforéza v polyakrylamidovém gelu MeSH
- haplotypy MeSH
- kyselina močová krev MeSH
- lidé MeSH
- mikrosatelitní repetice MeSH
- mutace MeSH
- sekvence nukleotidů MeSH
- western blotting MeSH
- xanthin moč MeSH
- xanthindehydrogenasa genetika MeSH
- xanthinoxidasa genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.
- MeSH
- anemie genetika metabolismus MeSH
- buněčné linie MeSH
- chronické selhání ledvin genetika metabolismus MeSH
- dítě MeSH
- dominantní geny MeSH
- dospělí MeSH
- genetická vazba MeSH
- hyperurikemie genetika metabolismus MeSH
- ledviny cytologie ultrastruktura MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- počítačová simulace MeSH
- předškolní dítě MeSH
- renin genetika metabolismus MeSH
- rodokmen MeSH
- sekvenční analýza DNA MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
50 stran ; 30 cm
Sborník textů, které se zaměřují na metody molekulární genetické a cytogenetické vyšetřovací metody. Součást projektu Metabolické vzdělávací centrum. Určeno odborné veřejnosti.
- MeSH
- cytogenetické vyšetření MeSH
- cytogenetika MeSH
- diagnostické techniky molekulární MeSH
- genetické testování MeSH
- molekulární biologie MeSH
- Publikační typ
- sborníky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- genetika, lékařská genetika
- molekulární biologie, molekulární medicína
- cytologie, klinická cytologie
- NLK Publikační typ
- brožury
- projekty
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
- financování organizované 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
Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.
- MeSH
- cystathionin-beta-synthasa genetika MeSH
- financování organizované MeSH
- frekvence genu MeSH
- genetická variace MeSH
- genetické testování MeSH
- genová konverze fyziologie MeSH
- haplotypy MeSH
- homocystinurie genetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Afrika MeSH
- Evropa MeSH
Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.
- MeSH
- bazální membrána patologie ultrastruktura MeSH
- biopsie MeSH
- dítě MeSH
- dna (nemoc) MeSH
- dospělí MeSH
- financování organizované MeSH
- genetická heterogenita MeSH
- genetická vazba MeSH
- hyperurikemie genetika metabolismus MeSH
- hypofýza cytologie MeSH
- imunohistochemie MeSH
- kultivované buňky MeSH
- ledvinové kanálky patologie ultrastruktura MeSH
- ledviny chirurgie metabolismus patologie ultrastruktura MeSH
- lidé MeSH
- lidské chromozomy, pár 16 MeSH
- missense mutace MeSH
- mladiství MeSH
- mukoproteiny genetika metabolismus moč MeSH
- mutační analýza DNA MeSH
- polycystické ledviny autozomálně dominantní genetika MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- rodokmen MeSH
- sekvence nukleotidů MeSH
- syndrom MeSH
- transfekce MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH