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Molecular Cell Oct 2018RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in...
RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven "kinetic proofreading" mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates. ATP binding facilitates dsRNA engagement but, interestingly, makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merten syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNA but, more importantly, drives RIG-I oligomerization through translocation, which we show to be regulated by helicase motif IVa. RIG-I translocates directionally from the dsRNA end into the stem region, and the 5'ppp end "throttles" translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Aortic Diseases; Cell Line; DEAD Box Protein 58; DEAD-box RNA Helicases; Dental Enamel Hypoplasia; Female; HEK293 Cells; Humans; Hydrolysis; Kinetics; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Protein Binding; RNA; RNA, Double-Stranded; Receptors, Antigen, T-Cell; Receptors, Immunologic; Ribosomes; Signal Transduction; Vascular Calcification
PubMed: 30270105
DOI: 10.1016/j.molcel.2018.08.021 -
American Journal of Medical Genetics.... Mar 2008The association of dentinogenesis imperfecta (DI) with a distinct form of chondrodysplasia in a boy was reported by Goldblatt et al. [1991; Am J Med Genet 39:170-172]...
The association of dentinogenesis imperfecta (DI) with a distinct form of chondrodysplasia in a boy was reported by Goldblatt et al. [1991; Am J Med Genet 39:170-172] and has been given the name of Goldblatt syndrome or odontochondrodysplasia (ODCD; OMIM#184260). Since the original description, only four further individuals have been reported (one sib pair and two unrelated cases). We report on an additional six individuals, including a second sib pair (brother and sister), with clinical and radiographic features that cluster and thus confirm the nosologic status of this entity. The main radiographic features are congenital platyspondyly with coronal clefts, severe metaphyseal changes particularly of the hands, wrists, and knees, mesomelic limb shortening, and coxa valga. The main physical signs are short stature, joint laxity, narrow chest, scoliosis, and DI. This combination of clinical and radiographic findings allows clear recognition of this syndrome in early childhood. Of note, the signs that are present in the newborn period are not entirely specific and the differential diagnosis includes spondylometaphyseal dysplasia (SMD) Sedaghatian type or platyspondylic lethal dysplasia (PSLD) Torrance type. The occurrence of two sib pairs in a group of only 11 patients suggests an autosomal recessive inheritance pattern. Overmodification of cartilage-extracted collagen 2 has been reported in two sibs, but mutation analysis of COL2A1 as well as of COMP, FGFR3, RMRP, and SBDS in one or more patients have given negative results, and the molecular etiology is as yet unknown.
Topics: Adolescent; Bone and Bones; Child, Preschool; Female; Hand; Humans; Infant; Lower Extremity; Male; Odontodysplasia; Osteochondrodysplasias; Pelvis; Radiography
PubMed: 18241073
DOI: 10.1002/ajmg.a.32214 -
American Journal of Human Genetics Feb 2015Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma,...
Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.
Topics: Adult; Aortic Diseases; Base Sequence; Cells, Cultured; Child, Preschool; DEAD Box Protein 58; DEAD-box RNA Helicases; Dental Enamel Hypoplasia; Exome; Female; Genes, Dominant; Glaucoma; Humans; Male; Metacarpus; Models, Molecular; Molecular Sequence Data; Muscular Diseases; Musculoskeletal Abnormalities; Mutation, Missense; Odontodysplasia; Osteoporosis; Pedigree; Polymorphism, Single Nucleotide; Radiography; Receptors, Immunologic; Sequence Analysis, DNA; Vascular Calcification
PubMed: 25620203
DOI: 10.1016/j.ajhg.2014.11.019 -
Journal of Oral Science Jun 2010Oculodentodigital dysplasia is an extremely rare autosomal dominant pleiotropic disorder. The syndrome is characterized by abnormal facial features, central nervous...
Oculodentodigital dysplasia is an extremely rare autosomal dominant pleiotropic disorder. The syndrome is characterized by abnormal facial features, central nervous system involvement, syndactyly and clinodactyly of fourth and fifth fingers, dry and lusterless hair, generalized enamel hypoplasia and odontodysplasia. Combination of odontodysplasia, poor oral hygiene, and parental neglect can lead to extensive destruction of tooth structure and the treatment options become limited. Early diagnosis with a proper treatment plan and meticulous oral hygiene program helps eliminate the necessity of multiple tooth extractions. This case report describes the comprehensive dental treatment aimed at rehabilitation of function and aesthetics of the dentition in an 8-year-old boy with oculodentodigital dysplasia.
Topics: Child; Comprehensive Dental Care; Craniofacial Abnormalities; Dental Caries; Dental Enamel Hypoplasia; Dental Pulp Capping; Dental Restoration, Permanent; Follow-Up Studies; Humans; Male; Odontodysplasia; Patient Care Planning; Pulpitis; Root Canal Therapy; Tooth Abnormalities
PubMed: 20587963
DOI: 10.2334/josnusd.52.337 -
American Journal of Human Genetics Feb 2003Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and... (Comparative Study)
Comparative Study
Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. These channels consist of connexin family proteins that allow for diversity of channel composition and conductance properties. The human connexin 43 gene, or GJA1, is located at human chromosome 6q22-q23 within the candidate region for the oculodentodigital dysplasia locus. This autosomal dominant syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III and conductive deafness can occur in some cases, and cardiac abnormalities are observed in rare instances. We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. Sixteen different missense mutations and one codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of gja1 animal mutants, reported elsewhere, are compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia.
Topics: Adolescent; Adult; Child; Child, Preschool; Chromosomes, Human, Pair 6; Connexin 43; Conserved Sequence; Craniofacial Abnormalities; Eye Abnormalities; Female; Genotype; Heterozygote; Humans; Infant; Infant, Newborn; Limb Deformities, Congenital; Male; Models, Molecular; Mutation; Odontodysplasia; Sequence Homology, Amino Acid
PubMed: 12457340
DOI: 10.1086/346090 -
Indian Journal of Dentistry 2015Epidermal nevi are hamartomatous lesion and its association with other developmental defects particularly of the central nervous system, eye and skeletal system are well...
Epidermal nevi are hamartomatous lesion and its association with other developmental defects particularly of the central nervous system, eye and skeletal system are well recognized. We report a rare case of inflammatory linear verrucous epidermal nevus syndrome along with regional odontodysplasia; and to the best of our knowledge this is the second case reported in the literature.
PubMed: 26752881
DOI: 10.4103/0975-962X.160348 -
American Journal of Medical Genetics.... Jan 2022Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of...
Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome.
Topics: Aortic Diseases; Autoimmune Diseases of the Nervous System; Dental Enamel Hypoplasia; Humans; Interferon-Induced Helicase, IFIH1; Interferons; Japan; Male; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteoporosis; Vascular Calcification
PubMed: 34453469
DOI: 10.1002/ajmg.a.62478 -
Acta Stomatologica Croatica Mar 2018Molar-incisor-hypomineralisation (MIH) is a disturbance in dental development that commonly involves first permanent molars but permanent incisors may also be...
BACKGROUND
Molar-incisor-hypomineralisation (MIH) is a disturbance in dental development that commonly involves first permanent molars but permanent incisors may also be compromised. The prevalence of MIH in the literature varies between 2.5% and 40% of the world child population. Little information is gained on the prevalence of MIH among children in Spain.
AIM
The aim of this study was to investigate the prevalence of MIH among school children from Barcelona, Spain.
MATERIAL AND METHODS
A cross-sectional study which included 705 children, aged 6 -14 years and 11 months was carried out. Full mouth examinations were performed using the European Academy of Paediatric Dentistry (EAPD) criteria for the diagnosis of MIH.
RESULTS
A total of 56 cases of MIH were found, 22 (39.3%) boys and 34 (60.7%) girls. The prevalence was 7.94% (6.39% for boys and 9.41% for girls). MIH lesions were seen more often in girls than boys (χ = 4.9, p= 0.023) the male/female ratio being 1:1.54. Upper teeth were more prevalent than lower teeth in both genders with an upper/lower ratio of 1.86/1 for boys and 1.68/1 for girls.
CONCLUSION
Considered either by gender or by teeth, upper teeth and girls were ahead in our sample.
PubMed: 30033998
DOI: 10.15644/asc52/1/1 -
Journal of Pharmacy & Bioallied Sciences Aug 2015Regional odontodysplasia (RO) is an uncommon, developmental anomaly of the dental hard tissues that affects ectodermal and mesodermal dental components with...
Regional odontodysplasia (RO) is an uncommon, developmental anomaly of the dental hard tissues that affects ectodermal and mesodermal dental components with characteristic clinical and radiographic findings. Clinically, RO affects a particular segment in either or both dentitions in the maxilla or mandible or both jaws. Radiographic features have consistently demonstrated thin and defective layers of enamel and dentine, resulting in a faint, fuzzy outline, creating a ghost-like appearance. The RO etiology is uncertain; numerous factors have been suggested and considered as local trauma, irradiation, hypophosphatasia, hypocalcemia, hyperpyrexia. A case of RO in a 10-year-old girl whose chief complaint were forwardly placed upper front teeth and the absence of eruption of permanent teeth. Clinical and radiographic features are described.
PubMed: 26538974
DOI: 10.4103/0975-7406.163570 -
Journal (Canadian Dental Association) Oct 2006Regional odontodysplasia is an uncommon developmental anomaly affecting a localized area of the dentition. The affected teeth are often grossly malformed and develop...
Regional odontodysplasia is an uncommon developmental anomaly affecting a localized area of the dentition. The affected teeth are often grossly malformed and develop abscess soon after eruption. Although extractions are often required, in some milder cases the teeth may be retained for a long period. The treatment plan should be based on the degree of involvement as well as functional and esthetic needs in each case. This article describes a conservative treatment approach in a 10-year-old boy with regional odontodysplasia.
Topics: Child; Dental Restoration, Permanent; Humans; Male; Odontodysplasia
PubMed: 17049109
DOI: No ID Found