CONTEXT: Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date. OBJECTIVES: To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD). DESIGN, SETTINGS, AND PATIENTS: Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height -2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines. RESULTS: In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1). CONCLUSIONS: Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.
- MeSH
- dítě MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- genetická variace * MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé MeSH
- lidský růstový hormon terapeutické užití MeSH
- metaloendopeptidasy genetika MeSH
- mladiství MeSH
- poruchy růstu farmakoterapie epidemiologie genetika MeSH
- předškolní dítě MeSH
- prognóza MeSH
- prospektivní studie MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- receptor IGF typ 1 genetika MeSH
- rodokmen MeSH
- růstová ploténka účinky léků MeSH
- sekvenování exomu metody MeSH
- stupeň závažnosti nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- DNA vazebné proteiny genetika MeSH
- dysgeneze štítné žlázy * diagnostické zobrazování epidemiologie farmakoterapie patologie MeSH
- genetická predispozice k nemoci * epidemiologie MeSH
- genetické pozadí * MeSH
- hodnocení rizik MeSH
- incidence MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- nádory štítné žlázy genetika patologie MeSH
- prognóza MeSH
- proteasomový endopeptidasový komplex genetika MeSH
- stupeň závažnosti nemoci MeSH
- testy funkce štítné žlázy MeSH
- thyroxin terapeutické užití MeSH
- transkripční faktor PAX8 genetika MeSH
- transkripční faktory MeSH
- ultrasonografie dopplerovská metody MeSH
- vzácné nemoci MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- souhrny MeSH
Following stimulation, pancreatic β-cells must orchestrate a plethora of signalling events to ensure the appropriate release of insulin and maintenance of normal glucose homeostasis. Failure at any point in this cascade leads to impaired insulin secretion, elevated blood levels of glucose and eventually type 2 diabetes mellitus. Likewise, β-cell replacement or regeneration strategies for the treatment of both type 1 and type 2 diabetes mellitus might fail if the correct cell signalling phenotype cannot be faithfully recreated. However, current understanding of β-cell function is complicated because of the highly dynamic nature of their intracellular and intercellular signalling as well as insulin release itself. β-Cells must precisely integrate multiple signals stemming from multiple cues, often with differing intensities, frequencies and cellular and subcellular localizations, before converging these signals onto insulin exocytosis. In this respect, optical approaches with high resolution in space and time are extremely useful for properly deciphering the complexity of β-cell signalling. An increased understanding of β-cell signalling might identify new mechanisms underlying insulin release, with relevance for future drug therapy and de novo stem cell engineering of functional islets.
- MeSH
- beta-buňky metabolismus MeSH
- diabetes mellitus 2. typu genetika metabolismus MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- glukosa metabolismus MeSH
- hodnocení rizik MeSH
- homeostáza genetika MeSH
- incidence MeSH
- lidé MeSH
- sekrece inzulinu fyziologie MeSH
- senzitivita a specificita MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy 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.
- 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
- MeSH
- ankylózující spondylitida epidemiologie genetika MeSH
- autoimunitní nemoci genetika imunologie MeSH
- diagnostické techniky molekulární MeSH
- dna (nemoc) epidemiologie genetika MeSH
- dnavá artritida epidemiologie genetika MeSH
- genetická predispozice k nemoci epidemiologie genetika MeSH
- hyperurikemie epidemiologie genetika metabolismus MeSH
- incidence MeSH
- lidé MeSH
- psoriatická artritida epidemiologie genetika MeSH
- revmatické nemoci * genetika imunologie MeSH
- revmatoidní artritida epidemiologie genetika MeSH
- systémový lupus erythematodes epidemiologie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Graves' disease affects approximately 3 % of women and 0.5 % of men. The first-choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid-specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants.
- MeSH
- genetická predispozice k nemoci epidemiologie genetika MeSH
- Gravesova nemoc diagnóza epidemiologie genetika MeSH
- HLA antigeny genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- pilotní projekty MeSH
- prediktivní hodnota testů MeSH
- recidiva MeSH
- štítná žláza patologie fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Several lines of evidence implicate the endothelin (ET) system in the pathophysiology of DN. The aim of the present study was to analyze if genetic polymorphisms of the ET-1 (EDN1) gene affect susceptibility to DN in Caucasians with T2DM. MATERIALS AND METHODS: The study population consisted of 651 Caucasian subjects with T2DM of more than 10 years' duration: 276 patients with DN (cases) and 375 patients without evidence of DN (controls). Polymorphisms in ET-1 (EDN1) gene, rs5370, rs1476046, and rs3087459, were studied. RESULTS: Genotype distributions of the studied polymorphisms showed no significant difference between cases and controls. CONCLUSIONS: We provide evidence that the rs5370, rs1476046, and rs3087459 polymorphisms of EDN1 gene are not risk factors for DN in Caucasians with T2DM.
- MeSH
- běloši genetika MeSH
- diabetes mellitus 2. typu etnologie genetika patofyziologie MeSH
- diabetické nefropatie etnologie genetika patofyziologie MeSH
- dospělí MeSH
- endotelin-1 genetika MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- hodnocení rizik MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymorfismus genetický * MeSH
- průřezové studie MeSH
- referenční hodnoty MeSH
- retrospektivní studie MeSH
- senzitivita a specificita MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Kazuistika popisuje náhodně diagnostikovaný medulární karcinom štítné žlázy s familiárním výskytem a poukazuje na význam vyšetření kalcitoninemie u sonograficky podezřelých uzlů.
The case report describes a randomly diagnosed medullary thyroid carcinoma with familial occurrence and points to the importance of serum calcitonin examination in ultrasonically suspected nodes.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- genetické testování MeSH
- kalcitonin krev MeSH
- lidé MeSH
- lymfadenektomie metody MeSH
- medulární karcinom diagnostické zobrazování genetika chirurgie MeSH
- nádory štítné žlázy genetika chirurgie patologie MeSH
- thyroxin aplikace a dávkování MeSH
- tyreoidektomie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. METHODS: The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry for Chronic Myeloid Leukemia in Children and Adolescents. RESULTS: Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation, children with ACAs, and children with a variant t(9;22) translocation who were treated with imatinib as frontline therapy, the probability of progression-free survival (PFS) was 95% (95% confidence interval [CI], 91%-97%), 100%, and 75% (95% CI, 13%-96%), respectively, and the probability of overall survival (OS) was 98% (95% CI, 95%-100%), 100% (95% CI, 43%-98%), and 75% (95% CI, 13%-96%), respectively. No statistical difference was observed between the patients with classic cytogenetic findings and those with additional chromosomal abnormalities in terms of PFS and OS. CONCLUSIONS: In contrast to adults with CML, additional chromosomal abnormalities observed at diagnosis do not seem to have a significant prognostic impact. Cancer 2017;123:3609-16. © 2017 American Cancer Society.
- MeSH
- analýza přežití MeSH
- chromozomální aberace statistika a číselné údaje MeSH
- chronická myeloidní leukemie diagnóza farmakoterapie genetika mortalita MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- internacionalita MeSH
- Kaplanův-Meierův odhad MeSH
- kvantitativní polymerázová řetězová reakce metody MeSH
- lidé MeSH
- lidské chromozomy, pár 22 genetika MeSH
- lidské chromozomy, pár 9 genetika MeSH
- následné studie MeSH
- neparametrická statistika MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- registrace MeSH
- retrospektivní studie MeSH
- rozvrh dávkování léků MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
