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Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD. publishersversion published

In this study the authors present an update to theDepending on the preceding analysis, four different mutation detection methods were used. A commercial assay targeting the most common CF-causing mutations was performed as the first test followed by an allele specific PCR for CFTRdele2,3(21kb), Sanger sequencing and MLPA analysis of the coding region of theIn our recent study 27 different mutations were detected, including 2 novel ones (c.1037_1038insA and c.1394CT). Besides F508del (c.1521_1523delCTT), the following mutations were found at a frequency of ≥ 4.0%: W1282X (c.3846GA), N1303K (c.3909CG), CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb) and 2184insA (c.2052_2053insA). In addition, four mutations (G542X, Y1092X, 621+1GT, and 2143delT) were found in more than one allele.The updated database of Hungarian mutations not only enables to increase the efficiency of the existing diagnostic approach, but also provides a further refined basis for the introduction of the molecular newborn screening (NBS) program in Hungary.U ovoj studiji autori predstavljaju nove podatke dobijene izučavanjem profila mutacije CFTR u Mađarskoj uz pomoć podataka izabrane grupe od 45 pacijenata sa cističnom fibrozom (CF) iz različitih krajeva zemlje.U zavisnosti od prethodne analize, korišćene su četiri različite metode za detekciju mutacija. Prvo je rađen komercijalni test koji ciljano traga za najčešćim mutacijama koje izazivaju CF, posle čega su primenjeni PCR za CFTRdele2,3(21 kb), Sanger sekvenciranje i MLPA analiza kodirajućeg regiona gena CFTR.U našoj nedavnoj studiji otkriveno je 27 različitih mutacija, uključujući dve dotad nepoznate (c.1037_1038insA i c.1394CT). Pored F508del (c.1521 _1523delCTT), pronađene su sledeće mutacije sa učestalošću ≥ 4,0%: W1282X (c.3846GA), N1303K (c.3909CG), CFTRdele2,3(21kb) (c.54-5940_273+10250 del21kb) i 2184insA (c.2052_2053insA). Pored toga, četiri mutacije (G542X, Y1092X, 621+1GT i 2143 delT) nađene su u više od jednog alela.Baza podataka o mađarskim mutacijama dopunjena poslednjim informacijama ne samo da omogućava povećavanje efikasnosti postojećeg dijagnostičkog pristupa, već takođe pruža dodatno usavršen osnov za uvođenje programa molekularnog skrininga novorođenčadi (NBS) u Mađarskoj.

Mutations in the UMOD gene encoding uromodulin (Tamm-Horsfall glycoprotein) result in the autosomal dominant transmission of progressive renal insufficiency and hypo-uricosuric hyperuricemia leading to gout at an early age. The clinical appearance is characterized by renal insufficiency and gout occurring in the late teenage years, with end-stage kidney disease characteristically developing between 40 and 70 years of age. This report provides a long-term characterization of renal functional decline in three children from one family with a novel UMOD mutation (c.891T>G, p.C297W) who received allopurinol and a low protein diet. While renal functional decline is slow in individuals with UMOD mutations, it may appear early in life and be associated with marked hyperuricemia. Anemia was also noted in this family.

To accurately segment invasive ductal carcinomas (IDCs) from dynamic contrast-enhanced MRI (DCE-MRI) using time series analysis based on linear dynamic system (LDS) modeling.Quantitative segmentation methods based on black-box modeling and pharmacokinetic modeling are highly dependent on imaging pulse sequence, timing of bolus injection, arterial input function, imaging noise, and fitting algorithms. We modeled the underlying dynamics of the tumor by an LDS and used the system parameters to segment the carcinoma on the DCE-MRI. Twenty-four patients with biopsy-proven IDCs were analyzed. The lesions segmented by the algorithm were compared with an expert radiologist's segmentation and the output of a commercial software, CADstream. The results are quantified in terms of the accuracy and sensitivity of detecting the lesion and the amount of overlap, measured in terms of the Dice similarity coefficient (DSC).The segmentation algorithm detected the tumor with 90% accuracy and 100% sensitivity when compared with the radiologist's segmentation and 82.1% accuracy and 100% sensitivity when compared with the CADstream output. The overlap of the algorithm output with the radiologist's segmentation and CADstream output, computed in terms of the DSC was 0.77 and 0.72, respectively. The algorithm also shows robust stability to imaging noise. Simulated imaging noise with zero mean and standard deviation equal to 25% of the base signal intensity was added to the DCE-MRI series. The amount of overlap between the tumor maps generated by the LDS-based algorithm from the noisy and original DCE-MRI was DSC = 0.95.The time-series analysis based segmentation algorithm provides high accuracy and sensitivity in delineating the regions of enhanced perfusion corresponding to tumor from DCE-MRI.