A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). -- Case Presentation: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G > A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A > G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G > A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A > G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. --Conclusions: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.This investigation was supported by the Instituto de Salud Carlos III and the Fundacion Vasca de Innovacion e Investigacion Sanitarias (funds to ES)

HistoWeb - Etudier l'histologie dans une nouvelle écologie d'apprentissage

HistoWeb targets the transformation of the professional tool Cytomineinto a comprehensive and innovative teaching platform, valuing the notions of learning ecology and new learning dimensions seeking for lifelong competencies. The poster was released at the Digital Learning round table, organized by the European Commission around H2020 funding instruments and call 2 "ICT-20 Technologies for better human learning"Appel Germaine Tillio

Optimising platelet secretomes to deliver robust tissue specific regeneration

Promoting cell proliferation is the cornerstone of most tissue regeneration therapies. As platelet‐based applications promote cell division and can be customised for tissue‐specific efficacy, this makes them strong candidates for developing novel regenerative therapies. Therefore, the aim of this study was to determine if platelet releasate could be optimised to promote cellular proliferation and differentiation of specific tissues. Growth factors in platelet releasate were profiled for physiological and supra‐physiological platelet concentrations. We analysed the effect of physiological and supra‐physiological releasate on C2C12 skeletal myoblasts, H9C2 rat cardiomyocytes, human dermal fibroblasts (HDF), HaCaT keratinocytes and chondrocytes. Cellular proliferation and differentiation were assessed through proliferation assays, mRNA and protein expression. We show that supra‐physiological releasate is not simply a concentrated version of physiological releasate. Physiological releasate promoted C2C12, HDF and chondrocyte proliferation with no effect on H9C2 or HaCaT cells. Supra‐physiological releasate induced stronger proliferation in C2C12 and HDF cells compared to physiological releasate. Importantly, supra‐physiological releasate induced proliferation of H9C2 cells. The proliferative effects of skeletal and cardiac muscle cells were in part driven by VEGFα. Furthermore, supra‐physiological releasate induced differentiation of H9C2 and C2C12, HDF and keratinocyte differentiation. This study provides insights into the ability of releasate to promote muscle, heart, skin and cartilage cell proliferation and differentiation and highlights the importance of optimising releasate composition for tissue‐specific regeneration

Genes for hereditary sensory and autonomic neuropathies: a genotype–phenotype correlation

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning

Immersive digital games: the interfaces for next-generation e-learning?

peer reviewedThe intrinsic motivation to play, and therefore to learn, that might be provided by digital educational games teases researchers and developers. However, existing educational games often fail in their attempt to compete with commercial games and to provide successful learning. Often some learning is added to digital games or some gameplay is added to educational applications. Successful educational games, however, require merging professional game design with sound pedagogical strategies, creating a new hybrid format. Moreover, a methodology is required that allows continuously balancing gaming and learning challenges and the learner's abilities and knowledge in order to retain an immersive gaming experience. In this article we introduce approaches to game design and didactic design, as well as a framework for adaptive interventions in educational games.ELEKTRA (Enhanced Learning Experience and Knowledge Transfer

The post‐COVID‐19 future of digital learning in higher education: views from educators, students, and other professionals in six countries

Predictions about the post-pandemic future of digital learning vary among higher education scholars. Some foresee dramatic, revolutionary change while others speculate that growth in educational technology will be buffeted both by modest expansion and unevenness. To this debate we contribute evidence from four groups across six countries on four continents: college and university educators (n = 281), students (n = 4243), senior administrators (n = 15), and instructional design specialists (n = 43). Our focus is on the future of digital learning after the pandemic-induced pivot to emergency remote instruction. Using data from interviews and self-administered questionnaires, our findings reveal a high degree of congruency between respondent groups, with most envisioning more blended/hybrid instruction post-pandemic and some modest increases in fully online courses. Student opinion is more sceptical about future change than within the other groups. Among respondents in all groups there is little expectation for a full-blown, revolutionary change in online or digital learnin

The post-COVID-19 future of digital learning in higher education: Views from educators, students, and other professionals in six countries

Predictions about the post-pandemic future of digital learning vary among higher education scholars. Some foresee dramatic, revolutionary change while others speculate that growth in educational technology will be buffeted both by modest expansion and unevenness. To this debate we contribute evidence from four groups across six countries on four continents: college and university educators (n = 281), students (n = 4243), senior administrators (n = 15), and instructional design specialists (n = 43). Our focus is on the future of digital learning after the pandemic-induced pivot to emergency remote instruction. Using data from interviews and self-administered questionnaires, our findings reveal a high degree of congruency between respondent groups, with most envisioning more blended/hybrid instruction post-pandemic and some modest increases in fully online courses. Student opinion is more sceptical about future change than within the other groups. Among respondents in all groups there is little expectation for a full-blown, revolutionary change in online or digital learning. Practitioner notes What is already known about this topic Digital learning has been growing in higher education, although a digital disconnect continues whereby the availability of educational technology exceeds its application to learning. Expectations regarding technology-mediated learning post-COVID-19 are mixed, hampering planning for the future. Hesitancy about teaching or taking courses with some or full online components persists. What this paper adds A strong majority of respondents in higher education foresee the most growth in blended/hybrid forms of digital learning post-COVID-19. A solid percentage, between about two-thirds and three-quarters of faculty and students, envision learners and instructors taking or teaching more fully online courses post-pandemic. A strong congruency exists between faculty, students, senior administrators, and instructional design professionals in their ranking of scenarios for the future of digital learning. Implications for practice and/or policy Educational technology in higher learning will not return to a pre-COVID-19 normality—if a pre-COVID-19 ‘normal’ could even be defined. As post-pandemic institutional planning unfolds, it is important to reflect experiences and incorporate insights of instructors, students, and instructional designers. Successfully building on these insights, where more blended/hybrid learning is foreseen, requires a thoughtful integration of face-to-face learning and educational technology