358 research outputs found
A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle
No full textThe aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle
A large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle.
No full textBACKGROUND
Congenital bovine chondrodysplasia, also known as bulldog calf syndrome, is characterized by disproportionate growth of bones resulting in a shortened and compressed body, mainly due to reduced length of the spine and the long bones of the limbs. In addition, severe facial dysmorphisms including palatoschisis and shortening of the viscerocranium are present. Abnormalities in the gene collagen type II alpha 1 chain (COL2A1) have been associated with some cases of the bulldog calf syndrome. Until now, six pathogenic single-nucleotide variants have been found in COL2A1. Here we present a novel variant in COL2A1 of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of the COL2A1-related bulldog calf syndrome in cattle.
CASE PRESENTATION
The calf was aborted at gestation day 264 and showed generalized disproportionate dwarfism, with a shortened compressed body and limbs, and dysplasia of the viscerocranium; a phenotype resembling bulldog calf syndrome due to an abnormality in COL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1. Polymerase chain reaction analysis and Sanger sequencing confirmed the breakpoints of the deletion and its absence in the genomes of both parents.
CONCLUSIONS
The pathological and genetic findings were consistent with a case of "bulldog calf syndrome". The identified variant causing the syndrome was the result of a de novo mutation event that either occurred post-zygotically in the developing embryo or was inherited because of low-level mosaicism in one of the parents. The identified loss-of-function variant is pathogenic due to COL2A1 haploinsufficiency and represents the first structural variant causing bulldog calf syndrome in cattle. Furthermore, this case report highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for genetic disorders in cattle
MITOSTATIN, A NOVEL MITOCHONDRIAL PROTEIN, THAT ACTS AS A TUMOR SUPPRESSOR IN PROSTATE CANCER CELLS
No full textMitostatin is a novel putative tumor suppressor gene at chromosome 12q24.1. The 62-kD Mitostatin protein is expressed in most normal human tissues and its immunohistochemical staining is reduced in advanced stages primary breast and bladder tumors. Mitostatin expression negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27.To determine the role of Mitostatin in prostate cancer we transfected LNCaP, PC3, and DU145 prostate cancer cells with an expression vector encoding Mitostatin -V5 fusion protein or expressing the antisense cDNA of the coding sequence of Mitostatin. In addition, we silenced endogenous Mitostatin by siRNA strategies. Mitostatin expression in primary human prostate tumors was analyzed by immunohistochemistry using three tissue arrays (AccuMax Array - A222, A223 and A302) consisted of 293 0.6-mm cores.Our results demonstrate that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells in addition to induce a reduction in cell growth, significantly inhibits migration and invasion. Moreover, Mitostatin inhibits colony formation in soft-agar in PC3 and LNCaP cells and LNCaP tumorigenicity in nude mice. Conversely, targeting endogenous Mitostatin with siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells promotes transformation in both cell lines. Mitostatin immunohistochemical staining was absent in 35.5% of prostate tumor samples and its overall reduction was significantly associated with advanced stage disease.Our findings support the hypothesis that Mitostatin acts as a bona fide tumor suppressor and suggest that further investigations of Mitostatin as a useful clinical marker for diagnosis and prognosis in prostate tumors are warranted
Whole genome sequencing reveals candidate causal genetic variants for spastic syndrome in Holstein cattle
No full textBovine spastic syndrome (SS) is a progressive, adult-onset neuromuscular disorder (NMD). SS is inherited but the mode of inheritance is unclear. The aim of this study was to characterize the phenotype and to identify a possible genetic cause of SS by whole-genome sequencing (WGS) and focusing on protein-changing variants. Seven affected unrelated Holstein cattle of both sexes were referred for SS at a mean age of 5.3 years (S.D.+/- 1.1) showing intermittent spasm of the skeletal muscles of the pelvic girdle. Assuming monogenic recessive inheritance, analysis of the WGS data did not reveal any private variants common to all cases. Searching for homozygous rare variants considering each case individually, allowed the identification of a rare recessive likely pathogenic missense variant in TOR3A for one case with an allele frequency of 1.69% in a global Holstein population. In the remaining six SS cases, we identified seven potentially dominant de novo mutations or inherited alleles as private heterozygous, mostly missense, variants of uncertain significance involving seven different NMD candidate genes: MPEG1, LHX8, WHAMM, NGRN, TTN, ATP1A1, PCDH1. All eight candidate causal variants identified were predicted to be deleterious. This study describes for the first time WGS findings in confirmed cases of bovine SS and provides evidence for a heterogeneous genetic cause of SS in cattle
X-linked duchenne-type muscular dystrophy in Jack Russell Terrier associated with a partial deletion of the canine DMD gene
No full textA 9-month old male Jack Russell Terrier started showing paraparesis of the hindlimbs after a walk. Hospitalized, the dog went into cardiac arrest, and later died. Necroscopic examination revealed a severe thickness of the diaphragm, esophagus, and base of the tongue, leading to the diagnosis of muscular dystrophy. The histology confirmed the marked size variation, regeneration, and fibrosis replacement of the skeletal muscle fibers. Immunohistochemistry demonstrated the absence of dystrophin confirming the diagnosis. Transmission electron microscopy showed disarrangement of skeletal muscle fibers. Finally, whole-genome sequencing identified a ~368kb deletion spanning 19 exons of the canine dystrophin (DMD) gene. This pathogenic loss-of-function variant most likely explains the observed disease phenotype. The X-chromosomal variant was absent in seven controls of the same breed. Most likely, this partial deletion of the DMD gene was either transmitted on the maternal path within the family of the affected dog or arose de novo. This study revealed a spontaneous partial deletion in DMD gene in a Jack Russell Terrier showing a Duchenne-type muscular dystrophy due to non-functional dystrophin
A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers–Danlos Syndrome
No full textClassical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by variable degrees of skin hyperextensibility and fragility, atrophic scarring, and generalized joint hypermobility. The purpose of this study was to characterize the clinicopathological phenotype of a cEDS-affected Holstein calf and to identify the causative genetic variant associated with the disorder by whole-genome sequencing (WGS). A 3-day-old female Holstein calf was referred because of easily induced skin detachment and hyperextensibility in the neck. A complete clinical investigation was performed in the calf, dam, and maternal-grandmother. The calf and dam showed hyperextensibility of the neck skin and atrophic scarring; additionally, the calf presented skin fragility. Moreover, the histopathology of biopsies from the calf and its dam showed that the collagen bundles in affected skin areas were wavy, short, thin, and surrounded by edema and moderate to severe acute hemorrhages. Genetic analysis revealed a private heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and dam. This confirmed the diagnosis of cEDS and represents the first report of a causal variant for cEDS in cattle and the first COL5A2-related large animal model.
Genodermatoses represent inherited disorders of the skin that mostly follow a monogenic mode of inheritance. Heritable connective tissue disorders such as classical Ehlers–Danlos syndrome (cEDS) belong to this group of human rare diseases that sporadically occur in other species. Herein, affected cattle are reported showing skin lesions including cutis laxa clinically and pathologically resembling cEDS in humans. Microscopic findings in the deeper dermis were consistent with collagen dysplasia. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL5A2 gene. The COL5A2 gene is known to be associated with dominant inherited cEDS forms in mice and humans, but so far, it was not shown to cause a similar phenotype in domestic animals. The disease phenotype examined herein showed co-segregation with the identified missense variant within the maternal line across two generations and is most likely due to a spontaneous mutation event. Rare non-lethal disorders such as cEDS in livestock are mostly not diagnosed, but might affect animal welfare and thus lower the value of affected animals. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders
De novo stop-lost germline mutation in FGFR3 causes severe chondrodysplasia in the progeny of a Holstein bull
No full textEvaluating the effectiveness of a training program in a distance runner
No full textNázev práce: Hodnocení účinnosti tréninkového programu u vytrvalostního běžce Cíle práce: Cílem této práce bylo prokázání kompetencí řídit tréninkový proces vytrvalostního běžce v přípravě na trať půlmaratonu a maratonu. Úkoly práce byly sestavení tréninkového plánu na dané období. Hodnocení účinnosti plánu na základě laboratorních a terénních testů a dosažených výsledků. Metodika: Trénovanou osobou byl muž ve věku 36 let, který se dlouhodobě věnuje vytrvalostnímu běhu, trénující 5 - 6x týdně. Tréninkový plán byl vytvořen na 27 týdnů a rozdělen na 3 období, 7 mezocyklů a 27 mikrocyklů. Příprava byla zakončena maratonským závodem. Pravidelně byla vedena evidence zatížení. Kompenzace organismu po zatížení byla zjišťována měřením ranní hodnoty HRV. Pro řízení intenzity tréninků byl využíván běžecký wattmetr. V každém období proběhlo vyšetření spiroergometrie v laboratoři. Výsledky: Během sledovaného období se u probanda zvýšila naměřená hodnota VO2max o 4 ml/kg-1 /min-1 což znamenalo zlepšení o 4,92 %. Úroveň kritického výkonu se zvýšila o 12,32 % z 4,22 W/kg na 4,74 W/kg. Na trati půlmaratonu i maratonu byly překonány osobní maxima, ovšem na maratonské trati nebylo dosaženo očekávaných výsledků. Přesto lze říci, že tréninková příprava byla na základě výsledků i naměřených parametrů úspěšná. Klíčová...Title: Evaluating the effectiveness of a training program for an endurance runner Objectives: The aim of this thesis was to demonstrate the competencies to manage the training process of an endurance runner in preparation for the half-marathon and marathon distances. The tasks of the thesis were the creation of a training plan for the given period, and the evaluation of the plan's effectiveness based on laboratory and field tests, and achieved results. Methodology: The trained individual was a 36 year-old male who has been involved in endurance running long-term, training 5-6 times a week. The training plan was created for 27 weeks and divided into 3 periods, 7 mesocycles, and 27 microcycles. The preparation culminated in a marathon race. Load monitoring was conducted regularly. Compensation of the organism after exertion was assessed by measuring the morning HRV value. A running power meter was used to manage training intensity. A spiroergometry examination was performer in the laboratory in each period. Results: During the monitored period, the proband's measured VO2max value increased by 4 ml/kg-1 /min-1 , which represented an improvement of 4.92 %. The critical power level increased by 12.32% from 4.22W/kg to 4.74W/kg. Personal bests were achieved in both the half-marathon and marathon races,...Katedra atletiky, sportů a pobytu v příroděDepartment of Athletics and Outdoor SportsFakulta tělesné výchovy a sportuFaculty of Physical Education and Spor
Molecular genetics of bladder cancer: Targets for diagnosis and therapy
No full textTransitional cell carcinoma of the bladder is a common tumor. While most patients presenting superficial disease can be expected to do well following treatment, still many patients will return to our office with muscle invasive and metastatic disease. Survival in advanced bladder cancer is less than 50%. Tumors of similar histologic grade and stage have variable behavior, suggesting that genetic alterations must be present to explain the diverse behavior of bladder cancer. It is hoped that through the study of the subtle genetic alterations in bladder cancer, important prognostic and therapeutic targets can be exploited. Many new diagnostic tests and gene therapy approaches rely on the identification and targeting of these unique genetic alterations. A review of literature published on the molecular genetics of bladder cancer from 1970 to the present was conducted. A variety of molecular genetic alterations have been identified in bladder cancer. Oncogenes (H-ras, erbB-2, EGFR, MDM2, C-MYC, CCND1), tumor suppressor genes (p53, Rb, p21, p27/KIP1, p16, PTEN, STK15, FHIT, FEZI/LZTS1, bc10), telomerase, and methylation have all been studied in bladder cancer. Several have proven to be potentially useful clinical targets in the prognosis and therapy of bladder cancer such as staining for p53 and gene therapy strategies such as p53 and fezl. Clinical trials targeting HER2/neu and the EGFR pathways are underway. The UroVysion bladder cancer assay relies on FISH to detect genetic alterations in this disease. Continuing identification of the molecular genetic alterations in bladder cancer will enhance future diagnostic and therapeutic approaches to bladder cancer. Capitalizing on these alterations will allow early detection, providing important prognostic information and unique targets for gene therapy and other therapeutic approaches
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