Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

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

Molecular Basis of Hereditary Hyperuricaemic Nephropathies

Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2) are autosomal dominant tubulointerstitial nephropathies characterized by combinations of hyperuricaemia, gouty arthritis, progressive renal insufficiency, and in some but not all families, medullary cysts. The phenotypic expression of these diseases is inconsistent, overlaps and indicates broader genetic and allelic heterogeneity. Their pathophysiology was mainly unknown. Previous studies localized FJHN/MCKD genes to chromosomes 16p11 and 1q21. This thesis was primarily aimed at identification of molecular bases and mechanisms underlying FJHN/MCKD. To follow this aim, we focused on collection and characterization of FJHN/MCKD patients and families, identification of disease causing genes in affected families, characterisation of identified proteins and their mutated forms and the isolation and characterisation of interacting partners of newly identified proteins. We employed and established numerous molecular genetic, molecular biological and biochemical methods. We gathered one of the largest sets of families with FJHN/MCKD in the world. In about 26% of families we identified UMOD (uromodulin encoding) gene mutations and characterised by various approaches 6 uromodulin mutant proteins...

Procesní model obchodní společnosti

Cílem této práce je na příkladu konkrétní obchodní společnosti popsat tvorbu procesního modelu a vysvětlit přínosy procesního řízení. Práce ve své první části prezentuje procesní hnutí ve svém historickém a obsahovém kontextu. Zmíněn je především procesní reengineering (BPR) a standardy ISO 9000. Další část se podrobně věnuje metodice procesního řízení firmy IDS Scheer. Je popsán životní cyklus BPM (Business Process Management) ? od navázání na firemní strategii, přes modelování procesů a implementaci optimalizačních opatření až po procesní kontroling ? čímž je akcentován procesní pohled na BPM. Hlavní přínos této práce je v praktické části, kde jsou popsány a nástrojem Aris Toolset namodelovány všechny obchodní procesy konkrétní distribuční společnosti. Tato práce by tak pro svůj komplexní a zároveň praktický přístup k problematice procesního řízení mohla být užitečná pro řídící pracovníky, kteří mají zatím jen kusé či povrchní informace o této oblasti.Process management is frequently used term these days. The aim of this diploma thesis is to explain, what „process“ actually means, what has been the historical evolution, what are its alternatives, but mainly what are the benefits for the company. Even though the title of this thesis is „Process model of trading company“, its content goes further than that. Creation of company’s process model is only one part, even though important, of the process- based management of the company (Business Process Management, BPM). Moreover, the methods and procedures described in this thesis can be used almost in any company, not only in the trading one. The main contribution of this thesis is in its broad view of process management. This thesis deals with some topics, which at the first sight don’t even relate to BPM (ISO standards or Change Management). Nevertheless, after closer examination the link becomes obvious. Most of the methods described in the theoretical part of this document are later used in its practical part for the BPM implementation proposal in the concrete company. The read is thus given an option to immediately confront theory with reality and visualize sometimes very general theoretical procedures. This document is structured in 5 chapters. The first chapter introduces a reader to this thesis topic, reasons for its selection and the aims, benefits and limitations. The second chapter shows the meaning of process management in the broader context of related concepts. The aim of the third chapter is to show practical use of process management. The fourth chapter is dedicated to implementation proposal of BPM in specific company. First, the company is described and its main aspects analyzed, which enables to present the company strategy. Then, the most important company processes are modeled and described, together with their evaluation and optimization proposal. The benefits and advantages of BPM are outlined in the closing chapter

Procesní model obchodní společnosti

Process management is frequently used term these days. The aim of this diploma thesis is to explain, what „process“ actually means, what has been the historical evolution, what are its alternatives, but mainly what are the benefits for the company. Even though the title of this thesis is „Process model of trading company“, its content goes further than that. Creation of company’s process model is only one part, even though important, of the process- based management of the company (Business Process Management, BPM). Moreover, the methods and procedures described in this thesis can be used almost in any company, not only in the trading one. The main contribution of this thesis is in its broad view of process management. This thesis deals with some topics, which at the first sight don’t even relate to BPM (ISO standards or Change Management). Nevertheless, after closer examination the link becomes obvious. Most of the methods described in the theoretical part of this document are later used in its practical part for the BPM implementation proposal in the concrete company. The read is thus given an option to immediately confront theory with reality and visualize sometimes very general theoretical procedures. This document is structured in 5 chapters. The first chapter introduces a reader to this thesis topic, reasons for its selection and the aims, benefits and limitations. The second chapter shows the meaning of process management in the broader context of related concepts. The aim of the third chapter is to show practical use of process management. The fourth chapter is dedicated to implementation proposal of BPM in specific company. First, the company is described and its main aspects analyzed, which enables to present the company strategy. Then, the most important company processes are modeled and described, together with their evaluation and optimization proposal. The benefits and advantages of BPM are outlined in the closing chapter