CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤ -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

• MeSH
• databáze faktografické MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• kolagen typ XI genetika   MeSH
• kolagen nedostatek   genetika   MeSH
• lidé MeSH
• lidský růstový hormon nedostatek   terapeutické užití   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• poruchy růstu * farmakoterapie   epidemiologie   genetika   patologie   MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• růstová ploténka růst a vývoj   metabolismus   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

• MeSH
• HEK293 buňky MeSH
• homozygot MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• lidé MeSH
• mechanistické cílové místo rapamycinového komplexu 1 metabolismus   MeSH
• mechanistické cílové místo rapamycinového komplexu 2 metabolismus   MeSH
• missense mutace genetika   MeSH
• mutantní proteiny chemie   metabolismus   MeSH
• osteogeneze * MeSH
• parathormon metabolismus   MeSH
• protein podobný parathormonu metabolismus   MeSH
• proteinkinasy chemie   nedostatek   genetika   metabolismus   MeSH
• proteolýza MeSH
• růstová ploténka metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce * MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• typy dědičnosti genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.

• MeSH
• achondroplazie genetika   patofyziologie   MeSH
• buňky NIH 3T3 MeSH
• chondrocyty metabolismus   MeSH
• chrupavka metabolismus   MeSH
• cilie patologie   fyziologie   MeSH
• ciliopatie genetika   patofyziologie   MeSH
• fenotyp MeSH
• fibroblastové růstové faktory metabolismus   MeSH
• lidé MeSH
• myši MeSH
• primární buněčná kultura MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   metabolismus   MeSH
• růstová ploténka metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• thanatoforní dysplazie genetika   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Plant cytokinesis is initiated in a transient membrane compartment, the cell plate, and completed by a process of maturation during which the cell plate becomes a cross wall. How the transition from juvenile to adult stages occurs is poorly understood. In this study, we monitor the Arabidopsis transport protein particle II (TRAPPII) and exocyst tethering complexes throughout cytokinesis. We show that their appearance is predominantly sequential, with brief overlap at the onset and end of cytokinesis. The TRAPPII complex is required for cell plate biogenesis, and the exocyst is required for cell plate maturation. The TRAPPII complex sorts plasma membrane proteins, including exocyst subunits, at the cell plate throughout cytokinesis. We show that the two tethering complexes physically interact and propose that their coordinated action may orchestrate not only plant but also animal cytokinesis.

• MeSH
• Arabidopsis cytologie   fyziologie   MeSH
• cytokineze fyziologie   MeSH
• cytoplazmatické vezikuly metabolismus   MeSH
• exocytóza fyziologie   MeSH
• mikrotubuly metabolismus   MeSH
• molekulární modely MeSH
• proteiny huseníčku metabolismus   MeSH
• růstová ploténka cytologie   metabolismus   MeSH
• vezikulární transportní proteiny metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to-ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification.

• MeSH
• buněčná diferenciace * MeSH
• chondrocyty metabolismus   patologie   MeSH
• fetální proteiny nedostatek   metabolismus   MeSH
• filaminy nedostatek   metabolismus   MeSH
• fyziologická kalcifikace MeSH
• hypertrofie MeSH
• jaderné proteiny nedostatek   metabolismus   MeSH
• lidé MeSH
• mikrofilamentové proteiny nedostatek   metabolismus   MeSH
• myši knockoutované MeSH
• proliferace buněk MeSH
• receptor parathormonu typ 1 metabolismus   MeSH
• růstová ploténka metabolismus   patologie   MeSH
• transport proteinů MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• insulinu podobný růstový faktor I metabolismus   MeSH
• lidé MeSH
• pohlavní steroidní hormony farmakologie   metabolismus   MeSH
• puberta krev   metabolismus   MeSH
• růstová ploténka metabolismus   růst a vývoj   MeSH
• růstový hormon krev   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• souhrny MeSH

• MeSH
• chrupavka metabolismus   MeSH
• insulinu podobný růstový faktor I * biosyntéza   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• receptory somatotropinu * fyziologie   MeSH
• růstová ploténka * metabolismus   MeSH
• somatomediny * biosyntéza   fyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• souhrny MeSH