ABSTRACT
BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.
Subject(s)
Exanthema , Glaucoma, Open-Angle , Odontodysplasia , DEAD Box Protein 58/genetics , Exanthema/pathology , Glaucoma, Open-Angle/pathology , Humans , Interferons/genetics , Metacarpus/pathology , Odontodysplasia/genetics , Odontodysplasia/pathology , Receptors, ImmunologicABSTRACT
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.
Subject(s)
Aortic Diseases/genetics , Autoimmune Diseases of the Nervous System/genetics , Dental Enamel Hypoplasia/genetics , Interferon-Induced Helicase, IFIH1/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Mutation , Nervous System Malformations/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Computational Biology , Humans , Hydrogen Bonding , Interferon-Induced Helicase, IFIH1/physiology , Molecular Conformation , Molecular Dynamics Simulation , Mutant Proteins/genetics , Mutation, Missense , Phenotype , Principal Component Analysis , RNA/metabolism , ThermodynamicsABSTRACT
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.
Subject(s)
Aortic Diseases/genetics , Dental Enamel Hypoplasia/genetics , Femur Head Necrosis/genetics , Interferons/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Skin Abnormalities/genetics , Vascular Calcification/genetics , Adult , Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Aortic Diseases/complications , Aortic Diseases/pathology , CD56 Antigen/genetics , Dental Enamel Hypoplasia/complications , Dental Enamel Hypoplasia/pathology , Femur Head/pathology , Femur Head Necrosis/complications , Femur Head Necrosis/pathology , Humans , Male , Metacarpus/pathology , Muscular Diseases/complications , Muscular Diseases/pathology , Odontodysplasia/complications , Odontodysplasia/pathology , Osteoporosis/complications , Osteoporosis/pathology , Receptors, Cell Surface/genetics , Skin Abnormalities/pathology , Treatment Outcome , Vascular Calcification/complications , Vascular Calcification/pathologyABSTRACT
More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported. Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients. The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A. However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features. The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot. Another variant, c.2993_2994del; p.(Lys998Serfs*5), has been observed in two individuals with a possible common ancestor. In summary, although there are clinical and radiological characteristics common to all individuals, we demonstrate that the clinical spectrum of TRIP11-associated dysplasias is even more diverse than previously described and that common genetic variants may exist.
Subject(s)
Cytoskeletal Proteins/genetics , Odontodysplasia/genetics , Osteochondrodysplasias/genetics , Phenotype , Adult , Child , Female , Humans , Loss of Function Mutation , Male , Odontodysplasia/diagnostic imaging , Odontodysplasia/pathology , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/pathologyABSTRACT
The type I interferonopathies comprise a heterogenous group of monogenic diseases associated with a constitutive activation of type I interferon signaling.The elucidation of the genetic causes of this group of diseases revealed an alteration of nucleic acid processing and signaling.ADAR1 is among the genes found mutated in patients with this type of disorders.This enzyme catalyzes the hydrolytic deamination of adenosines in inosines within a double-stranded RNA target (RNA editing of A to I). This RNA modification is widespread in human cells and deregulated in a variety of human diseases, ranging from cancers to neurological abnormalities.In this review, we briefly summarize the knowledge about the RNA editing alterations occurring in patients with mutations in ADAR1 gene and how these alterations might cause the inappropriate IFN activation.
Subject(s)
Genetic Diseases, Inborn/genetics , Interferon Type I/genetics , RNA Editing/physiology , Adenosine Deaminase/genetics , Aortic Diseases/genetics , Autoimmune Diseases of the Nervous System/genetics , Dental Enamel Hypoplasia/genetics , Humans , Immunity, Innate/genetics , Interferon Type I/metabolism , Metacarpus/abnormalities , Muscular Diseases/genetics , Nervous System Malformations/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , RNA, Double-Stranded/genetics , RNA-Binding Proteins/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Vascular Calcification/geneticsABSTRACT
Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2-/- transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.
Subject(s)
DEAD Box Protein 58/genetics , DEAD Box Protein 58/metabolism , Interferon Type I/immunology , Interleukin-17/metabolism , Interleukin-23 Subunit p19/metabolism , Psoriasis/pathology , Animals , Aortic Diseases/genetics , DNA-Binding Proteins/genetics , Dendritic Cells/immunology , Dental Enamel Hypoplasia/genetics , Epidermis/pathology , Hyperplasia/genetics , Hyperplasia/pathology , Janus Kinase Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Keratinocytes/cytology , Keratinocytes/pathology , Metacarpus/abnormalities , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscular Diseases/genetics , Neutrophils/immunology , Odontodysplasia/genetics , Osteoporosis/genetics , Piperidines/pharmacology , Psoriasis/genetics , Pyrimidines/pharmacology , T-Lymphocytes/immunology , Vascular Calcification/geneticsABSTRACT
Segmental odontomaxillary dysplasia (SOD) is a developmental condition of the middle and posterior maxilla featuring dysplastic bone overgrowth, dental abnormalities and, occasionally, various homolateral cutaneous manifestations. Herein, we describe an individual with maxillary abnormality akin to SOD and associated ipsilateral segmental odontomandibular dysplasia. Also, the result of the evaluation of lesional mandibular gingival tissue for overgrowth-related gene variants is reported. An 8-year-old girl presented clinically with congenital maxillary and mandibular alveolar soft tissue enlargement in the area of the premolars. A panoramic radiograph revealed abnormal trabeculation essentially similar to SOD in the maxilla and mandible with congenitally missing maxillary and mandibular first and second premolars and mandibular canines. Diagnostic mandibular bone biopsy was performed and lesional mandibular gingival hyperplastic tissue was obtained for variant analysis of somatic overgrowth genes PIK3CA, AKT1, AKT3, GNAQ, GNA11, MTOR, PIK3R2. Cone beam computerized tomography (CBCT) disclosed osseous abnormalities on the left side of the maxilla and mandible and very mild osseous expansion in the mandible. Histologically, abnormal bone exhibiting prominent reversal lines was present and associated with fibrocollagenous tissue. Genomic DNA analysis disclosed PIK3CAc.1571G>A; pArg524Lys which was seen at a low mosaic level in the blood, indicating a post-zygotic change. Although this case may be a unique disorder, by sharing features with SOD, one can suggest the possibility of mandibular involvement in SOD. The presence of a PIK3CA variant may support the hypothesis that these segmental disorders could be part of the PIK3CA-related overgrowth spectrum.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Gingival Hyperplasia/genetics , Mandible/abnormalities , Maxilla/abnormalities , Odontodysplasia/genetics , Child , Female , Gingival Hyperplasia/congenital , Humans , Odontodysplasia/pathologyABSTRACT
Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.
Subject(s)
Aortic Diseases/genetics , Arteries/metabolism , Dental Enamel Hypoplasia/genetics , Heredity , Metabolism, Inborn Errors/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Odontodysplasia/genetics , Osteogenesis/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Animals , Aortic Diseases/complications , Aortic Diseases/metabolism , Arteries/pathology , Dental Enamel Hypoplasia/complications , Dental Enamel Hypoplasia/metabolism , Gaucher Disease/complications , Gaucher Disease/genetics , Gaucher Disease/metabolism , Genetic Predisposition to Disease , Humans , Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/metabolism , Metacarpus/metabolism , Muscular Diseases/complications , Muscular Diseases/metabolism , Odontodysplasia/complications , Odontodysplasia/metabolism , Osteoporosis/complications , Osteoporosis/metabolism , Phenotype , Risk Assessment , Risk Factors , Vascular Calcification/complications , Vascular Calcification/metabolism , Vascular Calcification/pathologySubject(s)
Aortic Diseases/genetics , Dental Enamel Hypoplasia/genetics , Heart Diseases/genetics , Interferon-Induced Helicase, IFIH1/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Adolescent , Adult , Aortic Diseases/complications , Aortic Diseases/pathology , Dental Enamel Hypoplasia/complications , Dental Enamel Hypoplasia/pathology , Female , Heart Diseases/physiopathology , Humans , Metacarpus/pathology , Muscular Diseases/complications , Muscular Diseases/pathology , Mutation/genetics , Odontodysplasia/complications , Odontodysplasia/pathology , Osteoporosis/complications , Osteoporosis/pathology , Vascular Calcification/complications , Vascular Calcification/pathology , Young AdultABSTRACT
BACKGROUNDS: Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the clinical phenotypes are diverse. This review briefly summarized the recent progresses of type I interferonopathy focusing on the clinical and molecular features, pathogeneses, diagnoses and potential therapies. DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals. RESULTS: Type I interferonopathies include Aicardi-Goutières syndrome, spondyloenchondro-dysplasia with immune dysregulation, stimulator of interferon genes-associated vasculopathy with onset in infancy, X-linked reticulate pigmentary disorder, ubiquitin-specific peptidase 18 deficiency, chronic atypical neutrophilic dermatitis with lipodystrophy, and Singleton-Merten syndrome originally. Other disorders including interferon-stimulated gene 15 deficiency and DNAse II deficiency are believed to be interferonopathies as well. Intracranial calcification, skin vasculopathy, interstitial lung disease, failure to thrive, skeletal development problems and autoimmune features are common. Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis. First generation Janus kinase inhibitors including baricitinib, tofacitinib and ruxolitinib are useful for disease control. Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome. CONCLUSIONS: Tremendous progress has been made for the discovery of type I interferonopathies and responsible genes. Janus kinase inhibitors and other agents have potential therapeutic roles. Future basic, translational and clinical studies towards disease monitoring and powerful therapies are warranted.
Subject(s)
Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Interferon Type I/immunology , Aortic Diseases/drug therapy , Aortic Diseases/genetics , Aortic Diseases/immunology , Autoimmune Diseases/genetics , Autoimmune Diseases of the Nervous System/drug therapy , Autoimmune Diseases of the Nervous System/genetics , Autoimmune Diseases of the Nervous System/immunology , Child , Dental Enamel Hypoplasia/drug therapy , Dental Enamel Hypoplasia/genetics , Dental Enamel Hypoplasia/immunology , Humans , Immunosuppressive Agents/therapeutic use , Interferon Type I/genetics , Metacarpus/abnormalities , Metacarpus/immunology , Muscular Diseases/drug therapy , Muscular Diseases/genetics , Muscular Diseases/immunology , Nervous System Malformations/drug therapy , Nervous System Malformations/genetics , Nervous System Malformations/immunology , Odontodysplasia/drug therapy , Odontodysplasia/genetics , Odontodysplasia/immunology , Osteoporosis/drug therapy , Osteoporosis/genetics , Osteoporosis/immunology , Phenotype , Protein Kinase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Vascular Calcification/drug therapy , Vascular Calcification/genetics , Vascular Calcification/immunologyABSTRACT
Singleton-Merten syndrome (SMS) is a type I interferonopathy characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, and psoriasis. A missense mutation in IFIH1 encoding a cytoplasmic viral RNA sensor MDA5 has recently been identified in the SMS patients as well as in patients with a monogenic form of lupus. We previously reported that Ifih1gs/+ mice express a constitutively active MDA5 and spontaneously develop lupus-like nephritis. In this study, we demonstrate that the Ifih1gs/+ mice also exhibit SMS-like bone abnormalities, including decreased bone mineral density and thin cortical bone. Histological analysis revealed a low number of osteoclasts, low bone formation rate, and abnormal development of growth plate cartilages in Ifih1gs/+ mice. These abnormalities were not observed in Ifih1gs/+ ã»Mavs-/- and Ifih1gs/+ ã»Ifnar1-/- mice, indicating the critical role of type I IFNs induced by MDA5/MAVS-dependent signaling in the bone pathogenesis of Ifih1gs/+ mice, affecting bone turnover. Taken together, our findings suggest the inhibition of type I IFN signaling as a possible effective therapeutic strategy for bone disorders in SMS patients.
Subject(s)
Aortic Diseases/metabolism , Bone Diseases/metabolism , Bone and Bones/abnormalities , Bone and Bones/metabolism , Dental Enamel Hypoplasia/metabolism , Interferon-Induced Helicase, IFIH1/metabolism , Metacarpus/abnormalities , Muscular Diseases/metabolism , Odontodysplasia/metabolism , Osteoporosis/metabolism , Vascular Calcification/metabolism , Animals , Aortic Diseases/genetics , Bone Diseases/genetics , Cartilage/metabolism , Dental Enamel Hypoplasia/genetics , Growth Plate/metabolism , Male , Metacarpus/metabolism , Mice , Mice, Inbred C57BL , Muscular Diseases/genetics , Mutation, Missense/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/geneticsABSTRACT
OBJECTIVE: Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of at least six teeth, excluding the third molars. Mutations in several genes including MSX1, PAX9, AXIN2, and WNT10A have been shown to cause non-syndromic tooth agenesis. Regional odontodysplasia (RO), also known as "ghost teeth," is a rare developmental anomaly of tooth formation affecting both dentitions. Some possible causes of RO have been suggested, yet the etiology remains unknown. Because the phenotypes of both oligodontia and RO co-occur in one Finnish family, the aim here was to investigate the genetic etiology of the two conditions. MATERIALS AND METHODS: A mutation screening of the genes MSX1, PAX9, AXIN2, and WNT10A was performed for the family members of a RO patient and family history of oligodontia. RESULTS: An initiation codon mutation of the PAX9 gene was found in the proband and segregating with oligodontia in the family. CONCLUSIONS: The etiology of regional odontodysplasia (RO) may be genetic and the same genes can be involved both in RO and tooth agenesis. CLINICAL RELEVANCE: Our results give new insights into the etiology of regional odontodysplasia, yet further results are needed.
Subject(s)
Anodontia , Odontodysplasia , PAX9 Transcription Factor , Anodontia/genetics , Codon, Initiator , Humans , MSX1 Transcription Factor , Mutation , Odontodysplasia/genetics , PAX9 Transcription Factor/genetics , PedigreeABSTRACT
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.
Subject(s)
Aortic Diseases/genetics , Dental Enamel Hypoplasia/genetics , Interferon-Induced Helicase, IFIH1/chemistry , Interferon-Induced Helicase, IFIH1/genetics , Metacarpus/abnormalities , Molecular Dynamics Simulation , Muscular Diseases/genetics , Mutation/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Amino Acid Motifs , Conserved Sequence , Humans , Hydrogen Bonding , Interferon-Induced Helicase, IFIH1/metabolism , Mutagenesis, Site-Directed , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Protein Domains , Protein Folding , Protein Structure, Secondary , Sequence Homology, Amino AcidABSTRACT
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.
Subject(s)
Aortic Diseases/genetics , DEAD Box Protein 58/genetics , Dental Enamel Hypoplasia/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Adult , Cell Line , Female , Gain of Function Mutation/genetics , HEK293 Cells , Humans , Interferon Type I/genetics , Male , Middle Aged , Phenotype , Promoter Regions, Genetic/genetics , Receptors, ImmunologicABSTRACT
Odonto-onycho-dermal dysplasia (OODD) is a rare autosomal recessive syndrome characterized by multiple ectodermal abnormalities. Mutations of the wingless-type MMTV integration site family member 10A (WNT10A) gene have been associated with OODD. To date, only 11 OODD-associated WNT10A mutations have been reported. In this report, we Characterized the clinical manifestations with focusing on dental phenotypes in four unrelated OODD patients. By Sanger sequencing, we identified five novel mutations in the WNT10A gene, including two homozygous nonsense mutations c.1176C>A (p.Cys392*) and c.742C>T (p.Arg248*), one homozygous frame-shift mutation c.898-899delAT (p.Ile300Profs*126), and a compound heterozygous mutation c.826T>A (p.Cys276Ser) and c.949delG (p.Ala317Hisfs*121). Our findings confirmed that bi-allelic mutations of WNT10A were responsible for OODD and greatly expanded the mutation spectrum of OODD. For the first time, we demonstrated that bi-allelic WNT10A mutations could lead to anodontia of permanent teeth, which enhanced the phenotypic spectrum of WNT10A mutations. Interestingly, we found that bi-allelic mutations in the WNT10A gene preferentially affect the permanent dentition rather the primary dentition, suggesting that the molecular mechanisms regulated by WNT10A in the development of permanent teeth and deciduous teeth might be different.
Subject(s)
Anodontia/genetics , Ectodermal Dysplasia/genetics , Genetic Predisposition to Disease , Odontodysplasia/genetics , Wnt Proteins/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Alleles , Anodontia/diagnostic imaging , Child , Codon, Nonsense/genetics , Ectodermal Dysplasia/diagnostic imaging , Ectodermal Dysplasia/physiopathology , Female , Frameshift Mutation/genetics , Homozygote , Humans , Male , Odontodysplasia/diagnostic imaging , Odontodysplasia/physiopathology , PhenotypeABSTRACT
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 (
Subject(s)
Adenosine Triphosphatases/chemistry , Adenosine Triphosphate/chemistry , Aortic Diseases/genetics , DEAD Box Protein 58/chemistry , Dental Enamel Hypoplasia/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , AAA Proteins/chemistry , AAA Proteins/genetics , Adenosine Triphosphatases/genetics , Adenosine Triphosphate/metabolism , Aortic Diseases/enzymology , Aortic Diseases/pathology , Cytosol/virology , DEAD Box Protein 58/genetics , Dental Enamel Hypoplasia/enzymology , Dental Enamel Hypoplasia/pathology , Humans , Hydrolysis , Immunity, Innate/genetics , Metacarpus/enzymology , Metacarpus/pathology , Muscular Diseases/enzymology , Muscular Diseases/pathology , Mutation , Odontodysplasia/enzymology , Odontodysplasia/pathology , Osteoporosis/enzymology , Osteoporosis/pathology , Protein Binding , Protein Conformation , RNA, Double-Stranded/chemistry , RNA, Double-Stranded/genetics , RNA, Viral/chemistry , RNA, Viral/genetics , Receptors, Immunologic , Vascular Calcification/enzymology , Vascular Calcification/pathologySubject(s)
Aortic Diseases/genetics , Dental Enamel Hypoplasia/genetics , Interferon-Induced Helicase, IFIH1/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Mutation, Missense/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Vascular Calcification/genetics , Aortic Diseases/pathology , Child, Preschool , Dental Enamel Hypoplasia/pathology , Female , Humans , Metacarpus/pathology , Muscular Diseases/pathology , Odontodysplasia/pathology , Osteoporosis/pathology , Polymorphism, Single Nucleotide/genetics , Vascular Calcification/pathology , Exome SequencingABSTRACT
PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
Subject(s)
Vascular Calcification/genetics , Abnormalities, Multiple/drug therapy , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Aortic Diseases/drug therapy , Aortic Diseases/genetics , Aortic Diseases/metabolism , Basal Ganglia Diseases/drug therapy , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/metabolism , Calcinosis/drug therapy , Calcinosis/genetics , Calcinosis/metabolism , Cartilage Diseases/drug therapy , Cartilage Diseases/genetics , Cartilage Diseases/metabolism , Dental Enamel Hypoplasia/drug therapy , Dental Enamel Hypoplasia/genetics , Dental Enamel Hypoplasia/metabolism , Diphosphates/metabolism , Enzyme Replacement Therapy , Gaucher Disease/drug therapy , Gaucher Disease/genetics , Gaucher Disease/metabolism , Hand Deformities, Congenital/drug therapy , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/metabolism , Humans , Hyperostosis, Cortical, Congenital/drug therapy , Hyperostosis, Cortical, Congenital/genetics , Hyperostosis, Cortical, Congenital/metabolism , Hyperphosphatemia/drug therapy , Hyperphosphatemia/genetics , Hyperphosphatemia/metabolism , Interferons/metabolism , Metacarpus/abnormalities , Metacarpus/metabolism , Muscular Diseases/drug therapy , Muscular Diseases/genetics , Muscular Diseases/metabolism , Odontodysplasia/drug therapy , Odontodysplasia/genetics , Odontodysplasia/metabolism , Osteoporosis/drug therapy , Osteoporosis/genetics , Osteoporosis/metabolism , Phosphates/metabolism , Progeria/drug therapy , Progeria/genetics , Progeria/metabolism , Pseudoxanthoma Elasticum/drug therapyABSTRACT
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 IFNß 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 IFNß 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.
Subject(s)
Aortic Diseases/genetics , Basal Ganglia Diseases/genetics , Calcinosis/genetics , Dental Enamel Hypoplasia/genetics , Glaucoma/genetics , Heart Valve Diseases/genetics , Interferon-Induced Helicase, IFIH1/genetics , Metacarpus/abnormalities , Muscular Diseases/genetics , Musculoskeletal Diseases/genetics , Odontodysplasia/genetics , Osteoporosis/genetics , Psoriasis/genetics , Vascular Calcification/genetics , Adolescent , Adult , Child , HEK293 Cells , Heterozygote , Humans , Middle Aged , Mutation , SyndromeABSTRACT
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.