• Klíčová slova
• ADTKD-MUC1, MUC1, autosomal dominant tubulointerstitial kidney disease, chronic kidney disease, massively parallel sequencing,
• MeSH
• intersticiální nefritida * diagnóza   genetika   MeSH
• lidé MeSH
• mucin 1 * genetika   MeSH
• mutace MeSH
• nemoci ledvin genetika   MeSH
• rodokmen MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 * MeSH

Polymorphism of the gene encoding mucin 1 (MUC1) is associated with skeletal and dental phenotypes in human genomic studies. Animals lacking MUC1 exhibit mild reduction in bone density. These phenotypes could be a consequence of modulation of bodily Ca homeostasis by MUC1, as suggested by the previous observation that MUC1 enhances cell surface expression of the Ca2+-selective channel, TRPV5, in cultured unpolarized cells. Using biotinylation of cell surface proteins, we asked whether MUC1 influences endocytosis of TRPV5 and another Ca2+-selective TRP channel, TRPV6, in cultured polarized epithelial cells. Our results indicate that MUC1 reduces endocytosis of both channels, enhancing cell surface expression. Further, we found that mice lacking MUC1 lose apical localization of TRPV5 and TRPV6 in the renal tubular and duodenal epithelium. Females, but not males, lacking MUC1 exhibit reduced blood Ca2+. However, mice lacking MUC1 exhibited no differences in basal urinary Ca excretion or Ca retention in response to PTH receptor signaling, suggesting compensation by transport mechanisms independent of TRPV5 and TRPV6. Finally, humans with autosomal dominant tubulointerstitial kidney disease due to frame-shift mutation of MUC1 (ADTKD-MUC1) exhibit reduced plasma Ca concentrations compared to control individuals with mutations in the gene encoding uromodulin (ADTKD-UMOD), consistent with MUC1 haploinsufficiency causing reduced bodily Ca2+. In summary, our results provide further insight into the role of MUC1 in Ca2+-selective TRP channel endocytosis and the overall effects on Ca concentrations.

• Klíčová slova
• Ca homeostasis, MUC1, TRPV5, TRPV6, mucin 1,
• MeSH
• buněčná membrána metabolismus   MeSH
• epitelové buňky metabolismus   MeSH
• kationtové kanály TRPV * metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mucin 1 * genetika   metabolismus   MeSH
• mutace MeSH
• myši MeSH
• sexuální faktory MeSH
• transport proteinů genetika   MeSH
• vápník * krev   metabolismus   moč   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• kationtové kanály TRPV * MeSH
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 * MeSH
• Trpv5 protein, mouse MeSH Prohlížeč
• Trpv6 protein, mouse MeSH Prohlížeč
• vápník * MeSH

INTRODUCTION: Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1. METHODS: This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals. RESULTS: Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were <5 U/mL in 22% of ADTKD-MUC1 patients, in 0/249 controls, and in 1% of the reference population. Plasma CA15-3 levels were >20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate. DISCUSSION/CONCLUSIONS: Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.

• Klíčová slova
• ADTKD-MUC1, Autosomal dominant tubulointerstitial kidney disease, CA15-3, Mucin-1, rs4072037,
• MeSH
• alely MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• intersticiální nefritida krev   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 1 krev   genetika   MeSH
• mutace MeSH
• prognóza MeSH
• průřezové studie MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• uromodulin genetika   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• biologické markery MeSH
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

• Klíčová slova
• diagnostic score, dominant kidney disease, gout, mucin-1, uromodulin,
• MeSH
• genetické testování MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace MeSH
• polycystické ledviny autozomálně dominantní * diagnóza   genetika   MeSH
• uromodulin genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

BACKGROUND: The occurrence of catamenial pneumothorax (CP) is rare, and the awareness of this diagnosis among physicians is insufficient. CP is highly correlated with pelvic endometriosis and remains the most common form of thoracic endometriosis syndrome. Circulating endometrial cells (CECs) have been previously detected in patients with pelvic endometriosis. Could CECs bring new insights into pneumothorax management? METHODS: This study aims to describe the occurrence and molecular characteristics of CECs in women with spontaneous pneumothorax (SP) (N = 20) with high suspicion of its catamenial character. CECs were enriched from peripheral blood by size-based separation (MetaCell). In addition to cytomorphology, gene expression profiling of captured cells was performed for 24 endometriosis-associated genes. RESULTS: CECs were present in all 20 patients with SP. Enriched CECs exhibited four character features: epithelial, stem cell-like, stroma-like, and glandular. However, not all of them were present in every sampling. Gene expression profiling revealed two distinct phenotypes of CECs in SP and/or CP: one of them refers to the diaphragm openings syndrome and the other to endometrial tissue pleural implantations. Comparisons of the gene expression profiles of CECs in pneumothorax (CECs-SP group) with CECs in pelvic endometriosis (CECs-non-SP group) have revealed significantly higher expression of HER2 in the CECs-SP group compared with the CECs-non-SP group. CONCLUSIONS: This proof-of-concept study demonstrates successful isolation and characterization of CECs in patients with SP. Identification of CECs in SP could alert endometriosis involvement and help early referral to gynecologic consultation for further examination and treatment.

• Klíčová slova
• MetaCell, biomarker, catamenial pneumothorax, circulating endometrial cells, culturing, endometriosis, gene expression profiling, in vitro, liquid biopsy,
• MeSH
• antigen CA-125 genetika   MeSH
• dospělí MeSH
• endometrióza krev   genetika   MeSH
• endometrium cytologie   MeSH
• keratin-18 genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladý dospělý MeSH
• mucin 1 genetika   MeSH
• nemoci pleury krev   genetika   MeSH
• pneumotorax krev   diagnóza   genetika   MeSH
• receptor erbB-2 genetika   MeSH
• studie případů a kontrol MeSH
• tekutá biopsie MeSH
• transkriptom MeSH
• vimentin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CA-125 MeSH
• ERBB2 protein, human MeSH Prohlížeč
• keratin-18 MeSH
• KRT18 protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• MUC1 protein, human MeSH Prohlížeč
• MUC16 protein, human MeSH Prohlížeč
• mucin 1 MeSH
• receptor erbB-2 MeSH
• VIM protein, human MeSH Prohlížeč
• vimentin MeSH

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

• Klíčová slova
• ADTKD, HNF-1B, MUC-1, UMOD, chronic kidney disease, frameshift, genetic, urinary smear,
• MeSH
• chronické selhání ledvin epidemiologie   genetika   patologie   MeSH
• dominantní geny * MeSH
• dospělí MeSH
• genetické testování statistika a číselné údaje   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• ledvinové kanálky patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace MeSH
• prevalence MeSH
• průřezové studie MeSH
• senioři MeSH
• uromodulin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Irsko epidemiologie   MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-beta MeSH
• HNF1B protein, human MeSH Prohlížeč
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

• Klíčová slova
• COP vesicles, ER stress, Golgi apparatus, cargo receptor, endoplasmic reticulum, epithelial cells, kidney, organoids, secretory pathway, unfolded protein response,
• MeSH
• benzamidy chemie   metabolismus   farmakologie   MeSH
• epitelové buňky cytologie   metabolismus   MeSH
• heptany farmakologie   terapeutické užití   MeSH
• imidazolinové receptory antagonisté a inhibitory   genetika   metabolismus   MeSH
• indukované pluripotentní kmenové buňky cytologie   metabolismus   MeSH
• ledviny cytologie   metabolismus   patologie   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• mucin 1 chemie   genetika   metabolismus   MeSH
• můstkové bicyklické sloučeniny farmakologie   terapeutické užití   MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci ledvin metabolismus   patologie   MeSH
• posunová mutace MeSH
• RNA interference MeSH
• signální dráha UPR účinky léků   MeSH
• transkripční faktor ATF6 metabolismus   MeSH
• vezikulární transportní proteiny chemie   metabolismus   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
• ATF6 protein, human MeSH Prohlížeč
• benzamidy MeSH
• BRD4780 MeSH Prohlížeč
• heptany MeSH
• imidazolinové receptory MeSH
• malá interferující RNA MeSH
• mucin 1 MeSH
• můstkové bicyklické sloučeniny MeSH
• NISCH protein, human MeSH Prohlížeč
• TMED9 protein, human MeSH Prohlížeč
• transkripční faktor ATF6 MeSH
• vezikulární transportní proteiny MeSH

Meningiomas are the most common primary extra-axial tumours of the central nervous system, however their metastatic spread beyond central nervous system is rare. Here we present the case of a 54-year-old male with anaplastic meningioma who, 1.5 years after initial diagnosis, developed a tumorous expansion in his left adrenal gland, showing octreotide uptake on scintigraphy. Clinical diagnosis of pheochromocytoma was made and left adrenalectomy performed. The tumour weighed 480 grams and measured up to 140 mm in diameter. On histologic examination, morphology consistent with the diagnosis of anaplastic meningioma was present, resembling the original central nervous system tumour. The tumour expressed strongly SSTR2A and focally epithelial membrane antigen, p63 and pancytokeratin (AE1/3). An extensive panel of neuronal and additional epithelial markers (SOX10, synaptophysin, chromogranin, inhibin, calretinin, BER-EP4, MOC31) was negative. The review of the literature on meningioma metastasising outside the central nervous system and on its differential diagnosis is provided.

• Klíčová slova
• meningioma, rare tumours, metastasis,
• MeSH
• diferenciální diagnóza MeSH
• lidé středního věku MeSH
• lidé MeSH
• meningeální nádory diagnóza   patologie   MeSH
• meningeom diagnóza   patologie   MeSH
• mucin 1 genetika   MeSH
• nádorové biomarkery analýza   MeSH
• nádory nadledvin sekundární   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH
• nádorové biomarkery MeSH

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

• Klíčová slova
• Autosomal Dominant Tubulo-Interstitial Kidney Disease, Inherited, MUC1, Mucin-1 Kidney Disease, diagnosis, immunostaining, kidney disease,
• MeSH
• genetická predispozice k nemoci epidemiologie   MeSH
• hodnocení rizik MeSH
• imunohistochemie MeSH
• incidence MeSH
• jehlová biopsie MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace genetika   MeSH
• polycystické ledviny autozomálně dominantní genetika   mortalita   patologie   MeSH
• prognóza MeSH
• registrace MeSH
• retrospektivní studie MeSH
• rodokmen MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH

Mucin 1 kidney disease, previously referred to as medullary cystic kidney disease type 1, is a rare hereditary kidney disease. It is one of several diseases now termed autosomal dominant tubulointerstitial kidney disease, as proposed by a KDIGO (Kidney Disease: Improving Global Outcomes) consensus report in 2014. Autosomal dominant tubulointerstitial kidney diseases share common clinical findings, such as autosomal dominant inheritance, bland urinary sediment, absent to mild proteinuria, and progressive loss of kidney function. Although the pathophysiology of mucin 1 kidney disease is still under investigation, genetic testing has been developed to detect the most well-known mutation, a single cytosine insertion into a string of 7 cytosines in the variable-number tandem repeat (VNTR) region of the MUC-1 gene. With this diagnostic tool, nephrologists can offer genetic counseling to affected families and monitor closely for progression of disease. We report a Hispanic patient with a strong family history of chronic kidney disease who tested positive for the MUC1 mutation.

• Klíčová slova
• Autosomal dominant tubulointerstitial kidney disease (ADTKD), MUC1 mutation, chronic kidney disease (CKD), frameshift mutation, hereditary kidney disease, kidney biopsy, mucin 1 kidney disease (MKD), proteinuria,
• MeSH
• biopsie MeSH
• DNA genetika   MeSH
• dospělí MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mucin 1 genetika   metabolismus   MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• polycystické ledviny autozomálně dominantní diagnóza   genetika   metabolismus   MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DNA MeSH
• MUC1 protein, human MeSH Prohlížeč
• mucin 1 MeSH