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
• Názvy látek
• messenger RNA MeSH
• SEC61A1 protein, human MeSH Prohlížeč
• translokační kanály SEC 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
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• renin MeSH

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

Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane.

• MeSH
• acetyltransferasy chemie   genetika   metabolismus   MeSH
• buněčné linie MeSH
• exony MeSH
• exprese genu MeSH
• klonování DNA MeSH
• komplementární DNA genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 8 genetika   MeSH
• mapování chromozomů MeSH
• molekulární sekvence - údaje MeSH
• mukopolysacharidóza III enzymologie   genetika   MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• myši MeSH
• polymerázová řetězová reakce MeSH
• rekombinantní fúzní proteiny genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sekvenční homologie aminokyselin MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetyltransferasy MeSH
• HGSNAT protein, human MeSH Prohlížeč
• komplementární DNA MeSH
• rekombinantní fúzní proteiny MeSH