Recent studies have uncovered profound and unexpected roles for a family of tiny regulatory RNAs, known as microRNAs (miRNAs), in the control of diverse aspects of hepatic function and dysfunction, ...including hepatocyte growth, stress response, metabolism, viral infection and proliferation, gene expression, and maintenance of hepatic phenotype. In liver cancer, misexpression of specific miRNAs suggests diagnostic and prognostic significance. Here, we review the biology of the most abundant miRNA in human liver, miR-122, and consider the diversity of its roles in the liver. We provide a compilation of all miRNAs expressed in the liver, and consider some possible therapeutic opportunities for exploiting miRNAs in the different settings of liver diseases.
Rare diseases affect approximately 350 million people worldwide. Delayed diagnosis is frequent due to lack of knowledge of most clinicians and a small number of expert centers. Consequently, ...computerized diagnosis support systems have been developed to address these issues, with many relying on rare disease expertise and taking advantage of the increasing volume of generated and accessible health-related data. Our objective is to perform a review of all initiatives aiming to support the diagnosis of rare diseases.
A scoping review was conducted based on methods proposed by Arksey and O'Malley. A charting form for relevant study analysis was developed and used to categorize data.
Sixty-eight studies were retained at the end of the charting process. Diagnosis targets varied from 1 rare disease to all rare diseases. Material used for diagnosis support consisted mostly of phenotype concepts, images or fluids. Fifty-seven percent of the studies used expert knowledge. Two-thirds of the studies relied on machine learning algorithms, and one-third used simple similarities. Manual algorithms were encountered as well. Most of the studies presented satisfying performance of evaluation by comparison with references or with external validation. Fourteen studies provided online tools, most of which aimed to support the diagnosis of all rare diseases by considering queries based on phenotype concepts.
Numerous solutions relying on different materials and use of various methodologies are emerging with satisfying preliminary results. However, the variability of approaches and evaluation processes complicates the comparison of results. Efforts should be made to adequately validate these tools and guarantee reproducibility and explicability.
Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, ...with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.
MicroRNAs (miRNAs) are small non-coding RNAs that associate with Argonaute proteins to regulate gene expression at the post-transcriptional level in the cytoplasm. However, recent studies have ...reported that some miRNAs localize to and function in other cellular compartments. Mitochondria harbour their own genetic system that may be a potential site for miRNA mediated post-transcriptional regulation. We aimed at investigating whether nuclear-encoded miRNAs can localize to and function in human mitochondria. To enable identification of mitochondrial-enriched miRNAs, we profiled the mitochondrial and cytosolic RNA fractions from the same HeLa cells by miRNA microarray analysis. Mitochondria were purified using a combination of cell fractionation and immunoisolation, and assessed for the lack of protein and RNA contaminants. We found 57 miRNAs differentially expressed in HeLa mitochondria and cytosol. Of these 57, a signature of 13 nuclear-encoded miRNAs was reproducibly enriched in mitochondrial RNA and validated by RT-PCR for hsa-miR-494, hsa-miR-1275 and hsa-miR-1974. The significance of their mitochondrial localization was investigated by characterizing their genomic context, cross-species conservation and instrinsic features such as their size and thermodynamic parameters. Interestingly, the specificities of mitochondrial versus cytosolic miRNAs were underlined by significantly different structural and thermodynamic parameters. Computational targeting analysis of most mitochondrial miRNAs revealed not only nuclear but also mitochondrial-encoded targets. The functional relevance of miRNAs in mitochondria was supported by the finding of Argonaute 2 localization to mitochondria revealed by immunoblotting and confocal microscopy, and further validated by the co-immunoprecipitation of the mitochondrial transcript COX3. This study provides the first comprehensive view of the localization of RNA interference components to the mitochondria. Our data outline the molecular bases for a novel layer of crosstalk between nucleus and mitochondria through a specific subset of human miRNAs that we termed 'mitomiRs'.
MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only ...hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense ...mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically ...characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C.
We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene.
We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature.
Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
Oral health is an inherent part of overall health as an important physiological crossroad of functions such as mastication, swallowing or phonation; and plays a central role in the life of ...relationships facilitating social and emotional expression.Our hypothesis was that in patients with rare diseases, access to dental care could be difficult because of the lack of professionals who know the diseases and accept to treat the patients, but also because some patients with cognitive and intellectual disabilities could not find adequate infrastructure to assist in managing their oral health.
This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. The transcripts were reviewed to identify key themes and interviews were performed until the data were saturated and no further themes emerged.
Twenty-nine patients from 7 to 24 years old were included in the study of which 15 patients had an intellectual delay. The results show that access to care is complicated more by aspects concerning intellectual disability than by the fact that the disease is rare. Oral disorders are also an obstacle to the maintenance of their oral health.
The oral health of patients with rare diseases, can be greatly enhanced by a pooling of knowledge between health professionals in the various sectors around the patient's care. It is essential that this becomes a focus of national public health action that promotes transdisciplinary care for the benefit of these patients.
Around 8000 rare diseases are currently defined. In the context of individual vulnerability and more specifically the one induced by rare diseases, ensuring oral health is a particularly important ...issue. The objective of the study is to evaluate the pattern of oral health care course for patients with any rare genetic disease. Description of oral phenotypic signs--which predict a theoretical dental health care course--and effective orientation into an oral healthcare were evaluated. We set up a retrospective cohort study to describe the consideration of patient oral health and potential orientation to an oral health care course who have at least been seen once between 1 January 2017 and 1 January 2020 in Necker Enfants Malades Hospital. We recruited patients from this study using the data warehouse, Dr WarehouseR (DrWH), from Necker-Enfants Malades Hospital. The study sample included 39 rare diseases, 2712 patients, with 54.7% girls and 45.3% boys. In the sample studied, 27.9% of patients had an acquisition delay or a pervasive developmental disorder. Among the patient files studied, oral and dental phenotypic signs were described for 18.40% of the patients, and an orientation in an oral healthcare was made in 15.60% of patients. The overall "network" effect was significantly associated with description of phenotypic signs (corrected p = 1.44e-77) and orientation to an oral healthcare (corrected p = 23.58e-44). Taking the Defiscience network (rare diseases of cerebral development and intellectual disability) as a reference for the odd ratio analysis, OSCAR, TETECOU, FILNEMUS, FIMARAD, MHEMO networks stand out from the other networks for their significantly higher consideration of oral phenotypic signs and orientation in an oral healthcare. To our knowledge, no study has explored the management of oral health in so many rare diseases. The expected benefits of this study are, among others, a better understanding, and a better knowledge of the oral care, or at least of the consideration of oral care, in patients with rare diseases. Moreover, with the will to improve the knowledge on genetic diseases, oral heath must have a major place in the deep patient phenotyping. Therefore, interdisciplinary consultations with health professionals from different fields are crucial.
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