BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.

• Klíčová slova
• Achondroplasia, FGFR3, ReACH, Registry, Skeletal dysplasia, Treatment,
• MeSH
• achondroplazie * epidemiologie   genetika   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mutace MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   MeSH
• registrace MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Slovenská republika MeSH
• Názvy látek
• receptor fibroblastových růstových faktorů, typ 3 MeSH

Mammalian limb development is driven by the integrative input from several signaling pathways; a failure to receive or a misinterpretation of these signals results in skeletal defects. The brachydactylies, a group of overlapping inherited human hand malformation syndromes, are mainly caused by mutations in BMP signaling pathway components. Two closely related forms, Brachydactyly type B2 (BDB2) and BDB1 are caused by mutations in the BMP antagonist Noggin (NOG) and the atypical receptor tyrosine kinase ROR2 that acts as a receptor in the non-canonical Wnt pathway. Genetic analysis of Nog and Ror2 functional interaction via crossing Noggin and Ror2 mutant mice revealed a widening of skeletal elements in compound but not in any of the single mutants, thus indicating genetic interaction. Since ROR2 is a non-canonical Wnt co-receptor specific for Wnt-5a we speculated that this phenotype might be a result of deregulated Wnt-5a signaling activation, which is known to be essential for limb skeletal elements growth and patterning. We show that Noggin potentiates activation of the Wnt-5a-Ror2-Disheveled (Dvl) pathway in mouse embryonic fibroblast (MEF) cells in a Ror2-dependent fashion. Rat chondrosarcoma chondrocytes (RCS), however, are not able to respond to Noggin in this fashion unless growth arrest is induced by FGF2. In summary, our data demonstrate genetic interaction between Noggin and Ror2 and show that Noggin can sensitize cells to Wnt-5a/Ror2-mediated non-canonical Wnt signaling, a feature that in cartilage may depend on the presence of active FGF signaling. These findings indicate an unappreciated function of Noggin that will help to understand BMP and Wnt/PCP signaling pathway interactions.

• Klíčová slova
• BMP signaling, Ror2, Wnt5a, brachydactyly, noggin, non-canonical Wnt pathways,
• Publikační typ
• časopisecké články MeSH

In-cell profiling enables the evaluation of receptor tyrosine activity in a complex environment of regulatory networks that affect signal initiation, propagation and feedback. We used FGF-receptor signaling to identify EGR1 as a locus that strongly responds to the activation of a majority of the recognized protein kinase oncogenes, including 30 receptor tyrosine kinases and 154 of their disease-associated mutants. The EGR1 promoter was engineered to enhance trans-activation capacity and optimized for simple screening assays with luciferase or fluorescent reporters. The efficacy of the developed, fully synthetic reporters was demonstrated by the identification of novel targets for two clinically used tyrosine kinase inhibitors, nilotinib and osimertinib. A universal reporter system for in-cell protein kinase profiling will facilitate repurposing of existing anti-cancer drugs and identification of novel inhibitors in high-throughput screening studies.

• Klíčová slova
• activity, cancer biology, cell biology, human, in cell, mouse, profiling, protein kinase, receptor tyrosine kinase, reporter,
• MeSH
• buněčné linie MeSH
• cytologické techniky metody   MeSH
• intravitální mikroskopie MeSH
• lidé MeSH
• myši MeSH
• onkogenní proteiny analýza   MeSH
• optické zobrazování MeSH
• proteinkinasy analýza   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• onkogenní proteiny MeSH
• proteinkinasy MeSH