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
- Publikační typ
- abstrakt z konference MeSH
Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.-274T>G and c.-307T>C). OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies.
- MeSH
- alely * MeSH
- dědičné dystrofie rohovky genetika MeSH
- DNA MeSH
- lidé MeSH
- mutace * MeSH
- promotorové oblasti (genetika) * MeSH
- rodokmen MeSH
- sekvence nukleotidů MeSH
- sekvenční homologie nukleových kyselin MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Some patients are susceptible to statin-associated myopathy (SAM) either because of genetic variations affecting statin uptake and metabolism, or because they predispose their carriers to muscular diseases. Among the frequent variants examined using the genome-wide association study approach, SLCO1B1 c.521T>C represents the only validated predictor of SAM in patients treated with high-dose simvastatin. Our aim was to ascertain the overall contribution of large copy-number variations (CNVs) to SAM diagnosed in 86 patients. CNVs were detected by whole genome genotyping using Illumina HumanOmni2.5 Exome BeadChips. Exome sequence data were used for validation of CNVs in SAM-related loci. In addition, we performed a specific search for CNVs in the SLCO1B region detected recently in Rotor syndrome subjects. Rare deletions possibly contributing to genetic predisposition to SAM were found in two patients: one removed EYS associated previously with SAM, the other was present in LARGE associated with congenital muscular dystrophy. Another two patients carried deletions in CYP2C19, which may predispose to clopidogrel-statin interactions. We found no common large CNVs potentially associated with SAM and no CNVs in the SLCO1B locus. Our findings suggest that large CNVs do not play a substantial role in the etiology of SAM.
- MeSH
- celogenomová asociační studie MeSH
- cytochrom P450 CYP2C19 genetika MeSH
- dospělí MeSH
- familiární hyperbilirubinemie genetika MeSH
- genetické lokusy MeSH
- genom lidský MeSH
- genotyp MeSH
- heterozygot MeSH
- kreatinkinasa krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoci svalů chemicky indukované genetika MeSH
- polypeptid C přenášející organické anionty genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- statiny škodlivé účinky MeSH
- studie případů a kontrol MeSH
- variabilita počtu kopií segmentů DNA genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články 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
AIM: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. METHODS: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. RESULTS: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. CONCLUSION: These findings support the role of rare variants and nominate loci for follow-up studies.
- MeSH
- celogenomová asociační studie MeSH
- chloridové kanály genetika MeSH
- dospělí MeSH
- exom genetika MeSH
- genetická variace MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- nemoci svalů chemicky indukované epidemiologie genetika MeSH
- polypeptid C přenášející organické anionty genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- statiny škodlivé účinky MeSH
- vzácné nemoci genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Hereditary breast cancer comprises a minor but clinically meaningful breast cancer (BC) subgroup. Mutations in the major BC-susceptibility genes are important prognostic and predictive markers; however, their carriers represent only 25% of high-risk BC patients. To further characterize variants influencing BC risk, we performed SOLiD sequencing of 581 genes in 325 BC patients (negatively tested in previous BRCA1/BRCA2/PALB2 analyses). In 105 (32%) patients, we identified and confirmed 127 truncating variants (89 unique; nonsense, frameshift indels, and splice site), 19 patients harbored more than one truncation. Forty-six (36 unique) truncating variants in 25 DNA repair genes were found in 41 (12%) patients, including 16 variants in the Fanconi anemia (FA) genes. The most frequent variant in FA genes was c.1096_1099dupATTA in FANCL that also show a borderline association with increased BC risk in subsequent analysis of enlarged groups of BC patients and controls. Another 81 (53 unique) truncating variants were identified in 48 non-DNA repair genes in 74 patients (23%) including 16 patients carrying variants in genes coding proteins of estrogen metabolism/signaling. Our results highlight the importance of mutations in the FA genes' family, and indicate that estrogen metabolism genes may reveal a novel candidate genetic component for BC susceptibility.
- MeSH
- jaderné proteiny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory prsu genetika MeSH
- oprava DNA genetika MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- protein FANCL genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.
- MeSH
- blefarofimóza diagnóza genetika MeSH
- dítě MeSH
- exony * MeSH
- faciální stigmatizace MeSH
- fenotyp MeSH
- histonacetyltransferasy genetika MeSH
- kongenitální hypotyreóza diagnóza genetika MeSH
- kraniofaciální abnormality diagnóza genetika MeSH
- ledviny abnormality MeSH
- lidé MeSH
- mentální retardace diagnóza genetika MeSH
- molekulární sekvence - údaje MeSH
- mutace * MeSH
- nestabilita kloubu diagnóza genetika MeSH
- patela abnormality MeSH
- psychomotorické poruchy diagnóza genetika MeSH
- sekvence nukleotidů MeSH
- skrotum abnormality MeSH
- urogenitální abnormality diagnóza genetika MeSH
- vrozené srdeční vady diagnóza genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH