RESUMO
Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.
Assuntos
Autofagia , Proteína DEAD-box 58 , Glaucoma , Pressão Intraocular , Malha Trabecular , Animais , Feminino , Humanos , Masculino , Camundongos , Doenças da Aorta , Autofagia/efeitos dos fármacos , Proteína DEAD-box 58/metabolismo , Proteína DEAD-box 58/genética , Hipoplasia do Esmalte Dentário , Glaucoma/patologia , Glaucoma/metabolismo , Glaucoma/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/metabolismo , Interferon beta/metabolismo , Pressão Intraocular/genética , Metacarpo/anormalidades , Camundongos Endogâmicos C57BL , Doenças Musculares , Mutação , Odontodisplasia , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Atrofia Óptica/patologia , Osteoporose , Linhagem , Receptores Imunológicos , Malha Trabecular/metabolismo , Malha Trabecular/efeitos dos fármacos , Calcificação VascularRESUMO
OBJECTIVE: This study aimed to evaluate the role of ruxolitinib in the interferon beta (IFN-ß) mediated osteoblast differentiation using human dental pulp stem cells (hDPSCs). DESIGN: hDPSCs from five deciduous teeth of healthy patients were stimulated by adding human recombinant IFN-ß protein (1 or 2 ng/ml) to the osteogenic differentiation induction medium. Substrate formation was determined using Alizarin Red staining, calcium concentration, and osteoblast marker expression levels. Ruxolitinib was used to inhibit the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway. Apoptosis was detected using terminal deoxynucleotidyl nick-end labeling (TUNEL) staining, and necroptosis was detected using propidium iodide staining and phosphorylated mixed lineage kinase domain-like protein (pMLKL) expression. RESULTS: In the IFN-ß-treated group, substrate formation was inhibited by a reduction in alkaline phosphatase (ALP) expression in a concentration-dependent manner. Although the proliferation potency was unchanged between the IFN-ß-treated and control groups, the cell number was significantly reduced in the experimental group. TUNEL-positive cell number was not significantly different; however, the protein level of necroptosis markers, interleukin-6 (IL-6) and pMLKL were significantly increased in the substrate formation. Cell number and ALP expression level were improved in the group administered ruxolitinib, a JAK-STAT inhibitor. Additionally, ruxolitinib significantly suppressed IL-6 and pMLKL levels. CONCLUSION: Ruxolitinib interfered with the IFN-ß-mediated necroptosis and osteogenic differentiation via the JAK-STAT pathway.
RESUMO
Background: Singleton-Merten syndrome type 1 (SGMRT1) is a rare autosomal dominant disorder caused by IFIH1 variations with blood vessel calcifications, teeth anomalies, and bone defects. Aim: We aimed to summarize the oral findings in SGMRT1 through a systematic review of the literature and to describe the phenotype of a 10-year-old patient with SGMRT1 diagnosis. Results: A total of 20 patients were described in the literature, in nine articles. Eight IFIH1 mutations were described in 11 families. Delayed eruption, short roots, and premature loss of permanent teeth were the most described features (100%). Impacted teeth (89%) and carious lesions (67%) were also described. Our patient, a 10-year-old male with Singleton-Merten syndrome, presented numerous carious lesions, severe teeth malposition, especially in the anterior arch, and an oral hygiene deficiency with a 100% plaque index. The panoramic X-ray did not show any dental agenesis but revealed very short roots and a decrease in the jaw alveolar bone height. The whole-genome sequencing analysis revealed a heterozygous de novo variant in IFIH1 (NM_022168.4) c.2465G > A (p.Arg822Gln). Conclusion: Confused descriptions of oral features occurred in the literature between congenital findings and "acquired" pathology, especially carious lesions. The dental phenotype of these patients encompasses eruption anomalies (delayed eruption and impacted teeth) and lack of root edification, leading to premature loss of permanent teeth, and it may contribute to the diagnosis. An early diagnosis is essential to prevent teeth loss and to improve the quality of life of these patients. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022300025].
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Singleton Merten syndrome (SMS) is one of the rarest multisystem genetic disorders that had been recognized in only a few cases. Patients who have this syndrome often present with calcification of the aorta and heart valves, dental dysplasia, joint calcification, distinct facial features, and growth and developmental delay. Other physical findings usually associated with SMS may include glaucoma, skeletal abnormalities including tendon rupture, muscle weakness, and arthropathy. In individuals with SMS, autoimmune diseases like psoriasis and systemic lupus erythematosus (SLE) can occur. In this case, we report a pre-term baby girl that developed congenital aortic calcification, renal hypertension, dental anomalies, multiple joint calcifications, atypical facial features, mild mental retardation, and developmental delay. At 17 years, the patient developed SLE based on positive antinuclear antibody (ANA) with clinical and immunological features like fever, malar rash, pericardial effusion, proteinuria, high ANA concentration, high anti-double-stranded DNA, low C4 complement, and presence of anti-Smith antibodies.
RESUMO
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/ß 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.
Assuntos
Interferon Tipo I , Osteoporose , Doenças da Aorta , Criança , Pré-Escolar , Hipoplasia do Esmalte Dentário , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Masculino , Metacarpo/anormalidades , Debilidade Muscular , Doenças Musculares , Nitrilas , Odontodisplasia , Osteoporose/genética , Pirazóis , Pirimidinas , Calcificação VascularRESUMO
Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.
Assuntos
Oftalmopatias Hereditárias/genética , Glaucoma/etiologia , Glaucoma/genética , Aniridia/genética , Aniridia/patologia , Doenças do Colágeno/complicações , Doenças do Colágeno/genética , Doenças do Colágeno/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Oftalmopatias Hereditárias/patologia , Glaucoma/patologia , Glaucoma de Ângulo Fechado/complicações , Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Fechado/patologia , Humanos , Hiperopia/complicações , Hiperopia/genética , Hiperopia/patologia , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Doenças Metabólicas/complicações , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Microftalmia/complicações , Microftalmia/genética , Microftalmia/patologia , Síndrome , Doenças Vasculares/complicações , Doenças Vasculares/genética , Doenças Vasculares/patologiaRESUMO
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 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: MDA5L372F, MDA5A452T, MDA5R779H, and MDA5R822Q 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 MDA5L372F and MDA5R822Q. 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.
Assuntos
Doenças da Aorta/genética , Doenças Autoimunes do Sistema Nervoso/genética , Hipoplasia do Esmalte Dentário/genética , Helicase IFIH1 Induzida por Interferon/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Mutação , Malformações do Sistema Nervoso/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Biologia Computacional , Humanos , Ligação de Hidrogênio , Helicase IFIH1 Induzida por Interferon/fisiologia , Conformação Molecular , Simulação de Dinâmica Molecular , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Fenótipo , Análise de Componente Principal , RNA/metabolismo , TermodinâmicaRESUMO
Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.
Assuntos
Doenças da Aorta/genética , Hipoplasia do Esmalte Dentário/genética , Necrose da Cabeça do Fêmur/genética , Interferons/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Anormalidades da Pele/genética , Calcificação Vascular/genética , Adulto , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Doenças da Aorta/complicações , Doenças da Aorta/patologia , Antígeno CD56/genética , Hipoplasia do Esmalte Dentário/complicações , Hipoplasia do Esmalte Dentário/patologia , Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/complicações , Necrose da Cabeça do Fêmur/patologia , Humanos , Masculino , Metacarpo/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Odontodisplasia/complicações , Odontodisplasia/patologia , Osteoporose/complicações , Osteoporose/patologia , Receptores de Superfície Celular/genética , Anormalidades da Pele/patologia , Resultado do Tratamento , Calcificação Vascular/complicações , Calcificação Vascular/patologiaRESUMO
The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation.
RESUMO
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Assuntos
Mutação com Ganho de Função , Estudos de Associação Genética , Genótipo , Helicase IFIH1 Induzida por Interferon/genética , Fenótipo , Alelos , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Helicase IFIH1 Induzida por Interferon/química , Masculino , Modelos Moleculares , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
PURPOSE: Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome. METHODS: We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C. RESULTS: We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon. CONCLUSIONS: DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
Assuntos
Doenças da Aorta/genética , Proteína DEAD-box 58/genética , Hipoplasia do Esmalte Dentário/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Adulto , Linhagem Celular , Feminino , Mutação com Ganho de Função/genética , Células HEK293 , Humanos , Interferon Tipo I/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Regiões Promotoras Genéticas/genética , Receptores ImunológicosRESUMO
Singleton-Merten syndrome, a critical and rare multifactorial disorder that is closely linked to R516Q mutation in MDA5 protein associated with an enhanced interferon response in the affected individual. In the present study, we provide conclusive key evidence on R516Q mutation and their connectivity towards sequence-structural basis dysfunction of MDA5 protein. Among the various mutations, we found R516Q is the most pathogenic mutation based on mutational signature Q-A-[RE]-G-R-[GA]-R-A-[ED]-[DE]-S-[ST]-Y-[TSAV]-L-V designed from our work. Further, we derived a distant ortholog for this mutational signature from which we identified 343 intra-residue interactions that fall communally in the position required to maintain the structural and functional integration of protein architecture. This identification served us to understand the critical role of hot spots in residual aggregation that holds a native form of folding conformation in the functional region. In addition, the long-range molecular dynamics simulation demarcated the residual dependencies of conformational transition in distinct regions (L29360-370α18, α19380-410L31, α21430-480L33-α22-L35 and α24510-520L38) occurring upon R516Q mutation. Together, our results emphasise that the dislocation of functional hot spots Pro229, Arg414, Val498, Met510, Ala513, Gly515 and Arg516 in MDA5 protein which is important for interior structural packing and fold arrangements. In a nutshell, our findings are perfectly conceded with other experimental reports and will have potential implications in immune therapeutical advancement for rare singleton-merten syndrome.
Assuntos
Doenças da Aorta/genética , Hipoplasia do Esmalte Dentário/genética , Helicase IFIH1 Induzida por Interferon/química , Helicase IFIH1 Induzida por Interferon/genética , Metacarpo/anormalidades , Simulação de Dinâmica Molecular , Doenças Musculares/genética , Mutação/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Motivos de Aminoácidos , Sequência Conservada , Humanos , Ligação de Hidrogênio , Helicase IFIH1 Induzida por Interferon/metabolismo , Mutagênese Sítio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Domínios Proteicos , Dobramento de Proteína , Estrutura Secundária de Proteína , Homologia de Sequência de AminoácidosRESUMO
Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type I interferon signaling platform. Here, we determined cryoelectron microscopy (cryo-EM) structures of MDA5-dsRNA filaments with different helical twists and bound nucleotide analogs at resolutions sufficient to build and refine atomic models. The structures identify the filament-forming interfaces, which encode the dsRNA binding cooperativity and length specificity of MDA5. The predominantly hydrophobic interface contacts confer flexibility, reflected in the variable helical twist within filaments. Mutation of filament-forming residues can result in loss or gain of signaling activity. Each MDA5 molecule spans 14 or 15 RNA base pairs, depending on the twist. Variations in twist also correlate with variations in the occupancy and type of nucleotide in the active site, providing insights on how ATP hydrolysis contributes to MDA5-dsRNA recognition.
Assuntos
Trifosfato de Adenosina/metabolismo , Microscopia Crioeletrônica , Helicase IFIH1 Induzida por Interferon/ultraestrutura , RNA de Cadeia Dupla/ultraestrutura , Células HEK293 , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Interferon beta/genética , Interferon beta/metabolismo , Simulação de Acoplamento Molecular , Mutação , Conformação de Ácido Nucleico , Conformação Proteica , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais , Relação Estrutura-AtividadeAssuntos
Doenças da Aorta/complicações , Insuficiência da Valva Aórtica/cirurgia , Hipoplasia do Esmalte Dentário/complicações , Metacarpo/anormalidades , Doenças Musculares/complicações , Odontodisplasia/complicações , Osteoporose/complicações , Substituição da Valva Aórtica Transcateter , Calcificação Vascular/complicações , Doenças da Aorta/diagnóstico , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/fisiopatologia , Hipoplasia do Esmalte Dentário/diagnóstico , Feminino , Humanos , Doenças Musculares/diagnóstico , Odontodisplasia/diagnóstico , Osteoporose/diagnóstico , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do Tratamento , Calcificação Vascular/diagnóstico , Adulto JovemRESUMO
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 (
Assuntos
Adenosina Trifosfatases/química , Trifosfato de Adenosina/química , Doenças da Aorta/genética , Proteína DEAD-box 58/química , Hipoplasia do Esmalte Dentário/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Proteínas AAA/química , Proteínas AAA/genética , Adenosina Trifosfatases/genética , Trifosfato de Adenosina/metabolismo , Doenças da Aorta/enzimologia , Doenças da Aorta/patologia , Citosol/virologia , Proteína DEAD-box 58/genética , Hipoplasia do Esmalte Dentário/enzimologia , Hipoplasia do Esmalte Dentário/patologia , Humanos , Hidrólise , Imunidade Inata/genética , Metacarpo/enzimologia , Metacarpo/patologia , Doenças Musculares/enzimologia , Doenças Musculares/patologia , Mutação , Odontodisplasia/enzimologia , Odontodisplasia/patologia , Osteoporose/enzimologia , Osteoporose/patologia , Ligação Proteica , Conformação Proteica , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/genética , RNA Viral/química , RNA Viral/genética , Receptores Imunológicos , Calcificação Vascular/enzimologia , Calcificação Vascular/patologiaRESUMO
Singleton-Merten syndrome (SMS) is an autosomal dominant, multi-system innate immune disorder characterized by early and severe aortic and valvular calcification, dental and skeletal abnormalities, psoriasis, glaucoma, and other varying clinical findings. Recently we identified a specific gain-of-function mutation in IFIH1, interferon induced with helicase C domain 1, segregated with this disease. SMS disease without hallmark dental anomalies, termed atypical SMS, has recently been reported caused by variants in DDX58, DEXD/H-box helicase 58. IFIH1 and DDX58 encode retinoic acid-inducible gene I (RIG-I)-like receptors family members melanoma differentiation-associated gene 5 and RIG-I, respectively. These cytosolic pattern recognition receptors function in viral RNA detection initiating an innate immune response through independent pathways that promote type I and type III interferon expression and proinflammatory cytokines. In this review, we focus on SMS as an innate immune disorder summarizing clinical features, molecular aspects of the pathogenetic pathway and discussing underlying mechanisms of the disease.
RESUMO
In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes, including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, we present a male child demonstrating recurrent febrile episodes, spasticity, and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with SMS. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease, including neurological involvement.
Assuntos
Doenças da Aorta/imunologia , Hipoplasia do Esmalte Dentário/imunologia , Inflamação/imunologia , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Metacarpo/anormalidades , Doenças Musculares/imunologia , Odontodisplasia/imunologia , Osteoporose/imunologia , Calcificação Vascular/imunologia , Doenças da Aorta/genética , Criança , Hipoplasia do Esmalte Dentário/genética , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Masculino , Metacarpo/imunologia , Doenças Musculares/genética , Mutação , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genéticaRESUMO
Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.
Assuntos
Doenças da Aorta/genética , Hipoplasia do Esmalte Dentário/genética , Heterogeneidade Genética , Helicase IFIH1 Induzida por Interferon/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Adulto , Doenças da Aorta/fisiopatologia , Hipoplasia do Esmalte Dentário/fisiopatologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Metacarpo/fisiopatologia , Doenças Musculares/fisiopatologia , Mutação de Sentido Incorreto , Odontodisplasia/fisiopatologia , Osteoporose/fisiopatologia , Fenótipo , Calcificação Vascular/fisiopatologiaRESUMO
The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding.
Assuntos
Trifosfato de Adenosina/metabolismo , RNA Helicases DEAD-box/metabolismo , RNA Viral/metabolismo , Linhagem Celular , Proteína DEAD-box 58 , Humanos , Hidrólise , Receptores Imunológicos , Especificidade por SubstratoRESUMO
Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.