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Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

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... Full description

Journal Title: American journal of human genetics 2015, Vol.96 (2), p.266-274
Main Author: Jang, Mi-Ae
Other Authors: Kim, Eun Kyoung , Now, Hesung , Nguyen, Nhung T.H , Kim, Woo-Jong , Yoo, Joo-Yeon , Lee, Jinhyuk , Jeong, Yun-Mi , Kim, Cheol-Hee , Kim, Ok-Hwa , Sohn, Seongsoo , Nam, Seong-Hyeuk , Hong, Yoojin , Lee, Yong Seok , Chang, Sung-A , Jang, Shin Yi , Kim, Jong-Won , Lee, Myung-Shik , Lim, So Young , Sung, Ki-Sun , Park, Ki-Tae , Kim, Byoung Joon , Lee, Joo-Heung , Kim, Duk-Kyung , Kee, Changwon , Ki, Chang-Seok
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/25620203
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title: Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
format: Article
creator:
  • Jang, Mi-Ae
  • Kim, Eun Kyoung
  • Now, Hesung
  • Nguyen, Nhung T.H
  • Kim, Woo-Jong
  • Yoo, Joo-Yeon
  • Lee, Jinhyuk
  • Jeong, Yun-Mi
  • Kim, Cheol-Hee
  • Kim, Ok-Hwa
  • Sohn, Seongsoo
  • Nam, Seong-Hyeuk
  • Hong, Yoojin
  • Lee, Yong Seok
  • Chang, Sung-A
  • Jang, Shin Yi
  • Kim, Jong-Won
  • Lee, Myung-Shik
  • Lim, So Young
  • Sung, Ki-Sun
  • Park, Ki-Tae
  • Kim, Byoung Joon
  • Lee, Joo-Heung
  • Kim, Duk-Kyung
  • Kee, Changwon
  • Ki, Chang-Seok
subjects:
  • ABC transporters
  • Adult
  • Aortic Diseases - genetics
  • Aortic Diseases - pathology
  • Base Sequence
  • Cells, Cultured
  • Child, Preschool
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases - chemistry
  • DEAD-box RNA Helicases - genetics
  • Dental Enamel Hypoplasia - genetics
  • Dental Enamel Hypoplasia - pathology
  • Exome - genetics
  • Female
  • Gene expression
  • Gene mutations
  • Genes, Dominant - genetics
  • Genetic disorders
  • Genetic research
  • Genetics
  • Genetics(clinical)
  • Glaucoma
  • Glaucoma - genetics
  • Humans
  • Male
  • Metacarpus - abnormalities
  • Metacarpus - pathology
  • Models, Molecular
  • Molecular Sequence Data
  • Muscular Diseases - genetics
  • Muscular Diseases - pathology
  • Musculoskeletal Abnormalities - diagnostic imaging
  • Musculoskeletal Abnormalities - genetics
  • Mutation
  • Mutation, Missense - genetics
  • Odontodysplasia - diagnostic imaging
  • Odontodysplasia - genetics
  • Odontodysplasia - pathology
  • Osteoporosis - genetics
  • Osteoporosis - pathology
  • Pedigree
  • Physiological aspects
  • Polymorphism, Single Nucleotide - genetics
  • Psoriasis
  • Radiography
  • Report
  • RNA-protein interactions
  • Sequence Analysis, DNA
  • Vascular Calcification - genetics
  • Vascular Calcification - pathology
ispartof: American journal of human genetics, 2015, Vol.96 (2), p.266-274
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleMutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
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creatorJang, Mi-Ae ; Kim, Eun Kyoung ; Now, Hesung ; Nguyen, Nhung T.H ; Kim, Woo-Jong ; Yoo, Joo-Yeon ; Lee, Jinhyuk ; Jeong, Yun-Mi ; Kim, Cheol-Hee ; Kim, Ok-Hwa ; Sohn, Seongsoo ; Nam, Seong-Hyeuk ; Hong, Yoojin ; Lee, Yong Seok ; Chang, Sung-A ; Jang, Shin Yi ; Kim, Jong-Won ; Lee, Myung-Shik ; Lim, So Young ; Sung, Ki-Sun ; Park, Ki-Tae ; Kim, Byoung Joon ; Lee, Joo-Heung ; Kim, Duk-Kyung ; Kee, Changwon ; Ki, Chang-Seok
creatorcontribJang, Mi-Ae ; Kim, Eun Kyoung ; Now, Hesung ; Nguyen, Nhung T.H ; Kim, Woo-Jong ; Yoo, Joo-Yeon ; Lee, Jinhyuk ; Jeong, Yun-Mi ; Kim, Cheol-Hee ; Kim, Ok-Hwa ; Sohn, Seongsoo ; Nam, Seong-Hyeuk ; Hong, Yoojin ; Lee, Yong Seok ; Chang, Sung-A ; Jang, Shin Yi ; Kim, Jong-Won ; Lee, Myung-Shik ; Lim, So Young ; Sung, Ki-Sun ; Park, Ki-Tae ; Kim, Byoung Joon ; Lee, Joo-Heung ; Kim, Duk-Kyung ; Kee, Changwon ; Ki, Chang-Seok
descriptionSingleton-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.
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languageeng
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subjectABC transporters ; Adult ; Aortic Diseases - genetics ; Aortic Diseases - pathology ; Base Sequence ; Cells, Cultured ; Child, Preschool ; DEAD Box Protein 58 ; DEAD-box RNA Helicases - chemistry ; DEAD-box RNA Helicases - genetics ; Dental Enamel Hypoplasia - genetics ; Dental Enamel Hypoplasia - pathology ; Exome - genetics ; Female ; Gene expression ; Gene mutations ; Genes, Dominant - genetics ; Genetic disorders ; Genetic research ; Genetics ; Genetics(clinical) ; Glaucoma ; Glaucoma - genetics ; Humans ; Male ; Metacarpus - abnormalities ; Metacarpus - pathology ; Models, Molecular ; Molecular Sequence Data ; Muscular Diseases - genetics ; Muscular Diseases - pathology ; Musculoskeletal Abnormalities - diagnostic imaging ; Musculoskeletal Abnormalities - genetics ; Mutation ; Mutation, Missense - genetics ; Odontodysplasia - diagnostic imaging ; Odontodysplasia - genetics ; Odontodysplasia - pathology ; Osteoporosis - genetics ; Osteoporosis - pathology ; Pedigree ; Physiological aspects ; Polymorphism, Single Nucleotide - genetics ; Psoriasis ; Radiography ; Report ; RNA-protein interactions ; Sequence Analysis, DNA ; Vascular Calcification - genetics ; Vascular Calcification - pathology
ispartofAmerican journal of human genetics, 2015, Vol.96 (2), p.266-274
rights
02015 The American Society of Human Genetics
1Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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42015 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2015 The American Society of Human Genetics
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1Kim, Eun Kyoung
2Now, Hesung
3Nguyen, Nhung T.H
4Kim, Woo-Jong
5Yoo, Joo-Yeon
6Lee, Jinhyuk
7Jeong, Yun-Mi
8Kim, Cheol-Hee
9Kim, Ok-Hwa
10Sohn, Seongsoo
11Nam, Seong-Hyeuk
12Hong, Yoojin
13Lee, Yong Seok
14Chang, Sung-A
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18Lim, So Young
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20Park, Ki-Tae
21Kim, Byoung Joon
22Lee, Joo-Heung
23Kim, Duk-Kyung
24Kee, Changwon
25Ki, Chang-Seok
title
0Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
1American journal of human genetics
addtitleAm J Hum Genet
descriptionSingleton-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.
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3Aortic Diseases - pathology
4Base Sequence
5Cells, Cultured
6Child, Preschool
7DEAD Box Protein 58
8DEAD-box RNA Helicases - chemistry
9DEAD-box RNA Helicases - genetics
10Dental Enamel Hypoplasia - genetics
11Dental Enamel Hypoplasia - pathology
12Exome - genetics
13Female
14Gene expression
15Gene mutations
16Genes, Dominant - genetics
17Genetic disorders
18Genetic research
19Genetics
20Genetics(clinical)
21Glaucoma
22Glaucoma - genetics
23Humans
24Male
25Metacarpus - abnormalities
26Metacarpus - pathology
27Models, Molecular
28Molecular Sequence Data
29Muscular Diseases - genetics
30Muscular Diseases - pathology
31Musculoskeletal Abnormalities - diagnostic imaging
32Musculoskeletal Abnormalities - genetics
33Mutation
34Mutation, Missense - genetics
35Odontodysplasia - diagnostic imaging
36Odontodysplasia - genetics
37Odontodysplasia - pathology
38Osteoporosis - genetics
39Osteoporosis - pathology
40Pedigree
41Physiological aspects
42Polymorphism, Single Nucleotide - genetics
43Psoriasis
44Radiography
45Report
46RNA-protein interactions
47Sequence Analysis, DNA
48Vascular Calcification - genetics
49Vascular Calcification - pathology
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7Jeong, Yun-Mi
8Kim, Cheol-Hee
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10Sohn, Seongsoo
11Nam, Seong-Hyeuk
12Hong, Yoojin
13Lee, Yong Seok
14Chang, Sung-A
15Jang, Shin Yi
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17Lee, Myung-Shik
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19Sung, Ki-Sun
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titleMutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
authorJang, Mi-Ae ; Kim, Eun Kyoung ; Now, Hesung ; Nguyen, Nhung T.H ; Kim, Woo-Jong ; Yoo, Joo-Yeon ; Lee, Jinhyuk ; Jeong, Yun-Mi ; Kim, Cheol-Hee ; Kim, Ok-Hwa ; Sohn, Seongsoo ; Nam, Seong-Hyeuk ; Hong, Yoojin ; Lee, Yong Seok ; Chang, Sung-A ; Jang, Shin Yi ; Kim, Jong-Won ; Lee, Myung-Shik ; Lim, So Young ; Sung, Ki-Sun ; Park, Ki-Tae ; Kim, Byoung Joon ; Lee, Joo-Heung ; Kim, Duk-Kyung ; Kee, Changwon ; Ki, Chang-Seok
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2Aortic Diseases - genetics
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5Cells, Cultured
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8DEAD-box RNA Helicases - chemistry
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28Molecular Sequence Data
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35Odontodysplasia - diagnostic imaging
36Odontodysplasia - genetics
37Odontodysplasia - pathology
38Osteoporosis - genetics
39Osteoporosis - pathology
40Pedigree
41Physiological aspects
42Polymorphism, Single Nucleotide - genetics
43Psoriasis
44Radiography
45Report
46RNA-protein interactions
47Sequence Analysis, DNA
48Vascular Calcification - genetics
49Vascular Calcification - pathology
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1Kim, Eun Kyoung
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7Jeong, Yun-Mi
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atitleMutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome
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abstractSingleton-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.
copUnited States
pubElsevier Inc
pmid25620203
doi10.1016/j.ajhg.2014.11.019
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