Primary cilia are dynamic compartments that regulate multiple aspects of cellular signaling. The production, maintenance, and function of cilia involve more than 1000 genes in mammals, and their mutations disrupt the ciliary signaling which manifests in a plethora of pathological conditions-the ciliopathies. Skeletal ciliopathies are genetic disorders affecting the development and homeostasis of the skeleton, and encompass a broad spectrum of pathologies ranging from isolated polydactyly to lethal syndromic dysplasias. The recent advances in forward genetics allowed for the identification of novel regulators of skeletogenesis, and revealed a growing list of ciliary proteins that are critical for signaling pathways implicated in bone physiology. Among these, a group of protein kinases involved in cilia assembly, maintenance, signaling, and disassembly has emerged. In this review, we summarize the functions of cilia kinases in skeletal development and disease, and discuss the available and upcoming treatment options.
- MeSH
- cilie metabolismus MeSH
- ciliopatie * genetika patologie MeSH
- homeostáza MeSH
- polydaktylie * genetika MeSH
- proteiny genetika MeSH
- savci MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Recently, it has been found that spontaneous mutation Lx (polydactyly-luxate syndrome) in the rat is determined by deletion of a conserved intronic sequence of the Plzf (Promyelocytic leukemia zinc finger protein) gene. In addition, Plzf is a prominent candidate gene for quantitative trait loci (QTLs) associated with cardiac hypertrophy and fibrosis in the spontaneously hypertensive rat (SHR). In the current study, we tested the effects of Plzf gene targeting in the SHR using TALENs (transcription activator-like effector nucleases). SHR ova were microinjected with constructs pTAL438/439 coding for a sequence-specific endonuclease that binds to target sequence in the first coding exon of the Plzf gene. Out of 43 animals born after microinjection, we detected a single male founder. Sequence analysis revealed a deletion of G that resulted in frame shift mutation starting in codon 31 and causing a premature stop codon at position of amino acid 58. The Plzftm1Ipcv allele is semi-lethal since approximately 95% of newborn homozygous animals died perinatally. All homozygous animals exhibited manifestations of a caudal regression syndrome including tail anomalies and serious size reduction and deformities of long bones, and oligo- or polydactyly on the hindlimbs. The heterozygous animals only exhibited the tail anomalies. Impaired development of the urinary tract was also revealed: one homozygous and one heterozygous rat exhibited a vesico-ureteric reflux with enormous dilatation of ureters and renal pelvis. In the homozygote, this was combined with a hypoplastic kidney. These results provide evidence for the important role of Plzf gene during development of the caudal part of a body-column vertebrae, hindlimbs and urinary system in the rat.
- MeSH
- alely MeSH
- DNA vazebné proteiny nedostatek genetika metabolismus MeSH
- exony MeSH
- genotyp MeSH
- genový targeting MeSH
- heterozygot MeSH
- homozygot MeSH
- krysa rodu rattus MeSH
- lokus kvantitativního znaku MeSH
- mnohočetné abnormality genetika patologie veterinární MeSH
- ocas abnormality MeSH
- polydaktylie genetika patologie veterinární MeSH
- posunová mutace MeSH
- potkani inbrední SHR MeSH
- sekvence aminokyselin MeSH
- sekvence nukleotidů MeSH
- TALENs genetika metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Congenital dislocation of the knee and congenital permanent dislocation of the patella are rare disorders usually associated with complex syndromes. Two cases of siblings, girl and boy, who had the same clinical phenotype of this disorder are presented. The diagnosis of Desbuquois dysplasia was made and its autosomal recessive heredity was confirmed by genetic analysis. DNA samples were sent for a molecular genetic analysis of the skeletal dysplasia. The girl was surgically treated for a complete (grade 3) anterior dislocation of the tibia on the femur in the first year of life. Redressing casts had not previously been applied to avoid the risk of damaging the epiphysis. The left knee was operated on by the method, as described by Curtis and Fisher, at the age of six months. The Kirschner wire was removed after one month and a plaster cast was applied to maintain the flexion required. At seven post-operative weeks physiotherapy was started with temporary use of a knee brace. The right knee was managed by a similar procedure at four months after the first surgery. Normal walking was achieved at the age of 21 months. Knee motion was symmetrically restricted, with 5 to 90 degrees of flexion. The boy was first seen at our out-patient department after his sister had achieved full walking ability. He was 10 years old at that time and presented with walking problems due to nearly 30 degrees of bilateral knee contractures. Permanent dislocation of both patellae was treated by the surgical technique described by Stanisavljevic. Revision surgery of the right knee due to patellar lateralization was required two years after the primary surgery; it was performed using the Campbell's technique. A corrective osteotomy of the left proximal tibia because of progressive genu valgum was carried out at four years following the first operation. At the last follow-up, the boy was 16 years old and the knee range of motion bilaterally was 0 to 120 degrees with good alignment of both knees. As a result of surgical treatment the two patients gained ability to walk without problems. Key words: bilateral congenital knee dislocation, patella, Desbuquois dysplasia, siblings, skeletal dysplasia, case report.
- MeSH
- dítě MeSH
- heterotopická osifikace diagnóza genetika MeSH
- kojenec MeSH
- kraniofaciální abnormality diagnóza genetika MeSH
- lidé MeSH
- luxace kolena vrozené chirurgie MeSH
- nanismus diagnóza genetika MeSH
- nestabilita kloubu diagnóza genetika MeSH
- polydaktylie diagnóza genetika MeSH
- sourozenci * MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR). METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions. RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain. CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment.
- MeSH
- hypertenze farmakoterapie genetika metabolismus MeSH
- krysa rodu rattus MeSH
- lipidy krev MeSH
- metabolický syndrom farmakoterapie genetika metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- ondansetron farmakologie MeSH
- polydaktylie genetika MeSH
- porucha glukózové tolerance farmakoterapie genetika metabolismus MeSH
- potkani inbrední BN MeSH
- potkani inbrední SHR * MeSH
- receptory serotoninové 5-HT3 genetika metabolismus MeSH
- savčí chromozomy MeSH
- serotoninové receptory 5-HT3 - antagonisté farmakologie MeSH
- zvířata kongenní MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Swanson et al tried to classify congenital hand anomalies according to the genetic cause and reported his classification in 1976. Since then, modifications on this classification were made and this classification was adopted by the International Federation of Society for Surgery of the Hand (IFSSH). It has been used widely as an IFSSH classification. It is relatively easy to use this classification, but it has its own limitations. The biggest one occurs in the classification of ectrodactyly. In order to solve these problems, the authors conducted clinical ad experimental studies and found that there should be at least four different types of teratogenic mechanisms of congenital defect of the digits. The first one is longitudinal deficiencies due to mesenchymal cell death in an early developmental stage; the second is abnormal induction of digital ray numbers in the hand plate including cleft hand, central polydactyly and syndactyly. The third is constriction band syndrome, which is caused after digital radiations have been formed, and the fourth is transverse deficiency, in which the critical period is not known. Based on these studies, the author modified IFSSH classification and it was adopted by the Japanese Society for Surgery of the Hand and is called Japanese modification of the IFSSH classification (Japanese modification). In this paper, the author introduced the Japanese modification of the IFSSH classification and described some recommendations.
- MeSH
- artrogrypóza genetika radiografie MeSH
- ektromelie genetika klasifikace radiografie MeSH
- kontraktura genetika klasifikace radiografie MeSH
- lidé MeSH
- palec ruky abnormality radiografie MeSH
- polydaktylie genetika klasifikace radiografie MeSH
- prsty ruky abnormality radiografie MeSH
- synostóza genetika klasifikace radiografie MeSH
- vrozené deformity horní končetiny klasifikace radiografie MeSH
- vrozené deformity ruky klasifikace radiografie MeSH
- vývojové onemocnění kostí genetika MeSH
- Check Tag
- lidé MeSH
Lx mutation in SHR.Lx rat manifests in homozygotes as hindlimb preaxial polydactyly. It was previously mapped to a chromosome 8 segment containing the Plzf gene. Plzf (promyelocytic leukemia zinc finger protein) influences limb development as a direct repressor of posterior HoxD genes. However, the Plzf coding sequence is intact in the Lx mutants. Using linkage mapping in F2 hybrids, we downsized the segment containing Lx to 155 kb and sequenced conserved noncoding elements (CNEs) inside. A 2,964-bp deletion in Plzf intron 2, never detected in control animals, is the only candidate for Lx. The deletion removes the most deeply conserved CNE in the 155-kb segment, suggesting a regulatory influence on Plzf expression. Correspondingly, using in situ hybridization and quantitative real-time polymerase chain reaction, we found a decrease of Plzf expression in Lx/Lx limb buds with concomitant anterior expansion of expression domains of its targets, Hoxd10-13 genes, in the absence of ectopic Sonic hedgehog expression. Upstream regulation of Plzf in limb buds is currently unknown. We present here the first candidate Plzf cis-regulatory sequence. (c) 2009 Wiley-Liss, Inc.
- MeSH
- delece genu MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- down regulace genetika MeSH
- embryo savčí embryologie metabolismus MeSH
- financování organizované MeSH
- introny genetika MeSH
- končetinové pupeny abnormality metabolismus MeSH
- konzervovaná sekvence MeSH
- krysa rodu rattus MeSH
- messenger RNA genetika MeSH
- nekódující RNA genetika MeSH
- polydaktylie genetika metabolismus MeSH
- rozvržení tělního plánu MeSH
- sekvence nukleotidů MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- lékařská genetika metody trendy MeSH
- polydaktylie genetika MeSH
- vývojová biologie metody trendy MeSH
- Publikační typ
- kongresy MeSH
- přehledy MeSH
- MeSH
- geny MeSH
- interpretace obrazu počítačem MeSH
- končetiny růst a vývoj MeSH
- polydaktylie genetika MeSH
- potkani inbrední SHR MeSH
- Publikační typ
- kongresy MeSH
