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Biomolecules Aug 2021Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by in humans. Single nucleotide polymorphisms in the...
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by in humans. Single nucleotide polymorphisms in the results in fatal genetic disorders such as Aicardi-Goutières syndrome and Singleton-Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5, MDA5, MDA5, and MDA5 and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5 and MDA5. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders.
Topics: Aortic Diseases; Autoimmune Diseases of the Nervous System; Computational Biology; Dental Enamel Hypoplasia; Humans; Hydrogen Bonding; Interferon-Induced Helicase, IFIH1; Metacarpus; Molecular Conformation; Molecular Dynamics Simulation; Muscular Diseases; Mutant Proteins; Mutation; Mutation, Missense; Nervous System Malformations; Odontodysplasia; Osteoporosis; Phenotype; Principal Component Analysis; RNA; Thermodynamics; Vascular Calcification
PubMed: 34439917
DOI: 10.3390/biom11081251 -
European Journal of Paediatric Dentistry Sep 2020Segmental odontomaxillary dysplasia is an uncommon nonhereditary growth disorder that affects the maxilla, gums and ipsilateral dentition. The disorder is diagnosed...
BACKGROUND
Segmental odontomaxillary dysplasia is an uncommon nonhereditary growth disorder that affects the maxilla, gums and ipsilateral dentition. The disorder is diagnosed mainly based on dental (over-retention of primary teeth, dental agenesis and diastemas) and bone findings (bone sclerosis, irregular trabeculation of immature bone and reduced maxillary sinus). This paper provides a case report.
CASE REPORT
A 5-year-old child with skin manifestations including hypertrichosis, facial erythema and pigmented nevus was diagnosed with type II segmental odontomaxillary dysplasia based on clinical, radiographic and histopathological analysis.
CONCLUSION
The skin findings can help with the suspicion of segmental odontomaxillary dysplasia, although the definitive diagnosis is typically established by a paediatric dentist based on clinical and radiological findings.
Topics: Child, Preschool; Diastema; Humans; Maxilla; Odontodysplasia; Skin Diseases; Tooth, Deciduous
PubMed: 32893658
DOI: 10.23804/ejpd.2020.21.03.14 -
ELife Jul 2018The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to...
The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (
Lässig et al., 2015 ), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.Topics: AAA Proteins; Adenosine Triphosphatases; Adenosine Triphosphate; Aortic Diseases; Cytosol; DEAD Box Protein 58; Dental Enamel Hypoplasia; Humans; Hydrolysis; Immunity, Innate; Metacarpus; Muscular Diseases; Mutation; Odontodysplasia; Osteoporosis; Protein Binding; Protein Conformation; RNA, Double-Stranded; RNA, Viral; Receptors, Immunologic; Vascular Calcification
PubMed: 30047865
DOI: 10.7554/eLife.38958 -
Medicina Oral, Patologia Oral Y Cirugia... Sep 2008Regional odontodysplasia (RO) is an unusual, non-hereditary anomaly of the dental hard tissues with characteristic clinical, radiographic and histological findings....
Regional odontodysplasia (RO) is an unusual, non-hereditary anomaly of the dental hard tissues with characteristic clinical, radiographic and histological findings. Clinically, RO affects the primary and permanent dentition in the maxilla and mandible or both jaws. Radiographically, there is a lack of contrast between the enamel dentin, both of which are less radiopaque than unaffected counterparts. Additionally, enamel and dentin layers are thin, giving the teeth a "ghost-like" appearance. Histologically, areas of hypocalcified enamel are visible and enamel prisms appear irregular in direction. Coronal dentin is fibrous, consisting of clefts and a reduced number of dentinal tubules; radicular dentin is generally more normal in structure and calcification. The RO etiology is uncertain; numerous factors have been suggested and considered as local trauma, irradiation, hypophosphatasia, hypocalcemia, hyperpyrexia. The treatment of RO has given rise to controversy. These cases require a continuous and multidisciplinary approach. Most clinicians advocate extracting the affected teeth as soon as possible and inserting a prosthetic replacement. Other clinicians prefer restorative procedures, if possible, to protect the affected erupted teeth. A case of RO in an 8 year-old male whose chief complaint was the absence of eruption of permanent teeth is presented. Clinical, radiographic and histological findings are described.
Topics: Child; Dentition, Permanent; Humans; Male; Odontodysplasia; Tooth Eruption, Ectopic; Tooth, Deciduous
PubMed: 18758400
DOI: No ID Found -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2017To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon...
OBJECTIVE
To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy.
METHODS
We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNβ reporter assay in HEK 293T cells.
RESULTS
We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNβ expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5.
CONCLUSION
These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.
Topics: Adolescent; Adult; Aortic Diseases; Basal Ganglia Diseases; Calcinosis; Child; Dental Enamel Hypoplasia; Glaucoma; HEK293 Cells; Heart Valve Diseases; Heterozygote; Humans; Interferon-Induced Helicase, IFIH1; Metacarpus; Middle Aged; Muscular Diseases; Musculoskeletal Diseases; Mutation; Odontodysplasia; Osteoporosis; Psoriasis; Syndrome; Vascular Calcification
PubMed: 28605144
DOI: 10.1002/art.40179 -
Contemporary Clinical Dentistry 2015Regional odontodysplasia (RO) is a rare developmental anomaly involving both mesodermal and ectodermal components in primary or permanent dentition. It affects the...
Regional odontodysplasia (RO) is a rare developmental anomaly involving both mesodermal and ectodermal components in primary or permanent dentition. It affects the maxilla and the mandible or both; however, maxilla is more commonly involved. This article reports the case of 33-month-old boy who came with the chief complaint of delayed eruption of mandibular teeth. Findings of clinical and radiographic examination were consistent with those of RO. Maxillary dentition was unaffected. Clinical and radiographic features and treatment options are discussed.
PubMed: 26097362
DOI: 10.4103/0976-237X.156054 -
Contemporary Clinical Dentistry 2022Regional odontodysplasia (RO), also called ghost teeth, is a rare nonhereditary developmental dental anomaly affecting the epidermal and mesenchymal tissues associated...
Regional odontodysplasia (RO), also called ghost teeth, is a rare nonhereditary developmental dental anomaly affecting the epidermal and mesenchymal tissues associated with the development of tooth which can affect both primary and permanent dentition. It can affect the child's overall quality of life and sometimes may lead to skeletal malocclusion. Management of such patients requires a multidisciplinary approach. Essix retainers are being widely used as retention appliances. Various modifications of this appliance are also being attempted. Thus, this article aims to focus on the use of Essix retainer as an interim prosthesis by modifying it with the incorporation of pontics to manage partial edentulousness and mild orthodontic corrections in a 7-year-old child diagnosed with bilateral RO.
PubMed: 36213853
DOI: 10.4103/ccd.ccd_434_21 -
Journal of Oral and Maxillofacial... Jan 2018Regional odontodysplasia (RO) also known as ghost teeth is a rare developmental anomaly affecting the mesodermal and ectodermal components of teeth with characteristic...
Regional odontodysplasia (RO) also known as ghost teeth is a rare developmental anomaly affecting the mesodermal and ectodermal components of teeth with characteristic clinical and radiographic findings. The enamel and dentin are hypomineralized and hypocalcified with short roots and open apices. The affected teeth have an abnormal morphology, meaning they are fragile and thin and liable to fracture and decay. Radiographically, there is a marked reduction in radiodensity with little distinction between the enamel and dentin, hence the term "ghost teeth." RO generally affects one particular segment in one or both arches of the maxilla or mandible and can affect both the primary and permanent dentition. We report a unique case of a 3-year-old female who presented to Alder Hey Children's Hospital acutely unwell with a left-sided cervicofacial swelling from RO affecting the entire portion of the left maxilla.
PubMed: 29491620
DOI: 10.4103/jomfp.JOMFP_146_17 -
Pediatric Rheumatology Online Journal Apr 2022Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor...
BACKGROUND
Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation.
CASE PRESENTATION
We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved.
CONCLUSIONS
JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight.
Topics: Aortic Diseases; Child; Child, Preschool; Dental Enamel Hypoplasia; Humans; Interferon Type I; Interferon-Induced Helicase, IFIH1; Male; Metacarpus; Muscle Weakness; Muscular Diseases; Nitriles; Odontodysplasia; Osteoporosis; Pyrazoles; Pyrimidines; Vascular Calcification
PubMed: 35410415
DOI: 10.1186/s12969-022-00686-7 -
The Journal of Clinical Pediatric... 2006A case of regional odontodysplasia in an 8 year-old male whose chief complaint was the absence of eruption of permanent teeth is presented. The regional odontodysplasia...
A case of regional odontodysplasia in an 8 year-old male whose chief complaint was the absence of eruption of permanent teeth is presented. The regional odontodysplasia is a rare development anomaly of the dental tissues that affects the primary and permanent dentitions involving several adjacent teeth without crossing the midline. The clinical, radiographic and histological aspects are described as well as the treatment accomplished through surgery and prosthetic rehabilitation.
Topics: Child; Denture, Partial; Humans; Male; Odontodysplasia; Radiography; Tooth Extraction; Tooth, Unerupted
PubMed: 16937862
DOI: 10.17796/jcpd.30.4.x52484224j37h4v5