A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

Frank Rutsch; Mary Macdougall; Changming Lu; Insa Buers; Olga Mamaeva; Yvonne Nitschke; Gillian I. Rice; Heidi Erlandsen; Hans Gerd Kehl; Holger Thiele; Peter Nürnberg; Wolfgang Höhne; Yanick J. Crow; Annette Feigenbaum; Raoul C. Hennekam

doi:https://doi.org/10.1016/j.ajhg.2014.12.014

A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

Frank Rutsch, Mary Macdougall, Changming Lu, Insa Buers, Olga Mamaeva, Yvonne Nitschke, Gillian I. Rice, Heidi Erlandsen, Hans Gerd Kehl, Holger Thiele, Peter Nürnberg, Wolfgang Höhne, Yanick J. Crow, Annette Feigenbaum, Raoul C. Hennekam

Research output: Contribution to journal › Article › Academic › peer-review

162 Citations (Scopus)

Abstract

Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutieres syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption

Original language	English
Pages (from-to)	275-282
Journal	American journal of human genetics
Volume	96
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2014.12.014
Publication status	Published - 2015

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https://doi.org/10.1016/j.ajhg.2014.12.014

Cite this

Rutsch, F., Macdougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., Rice, G. I., Erlandsen, H., Kehl, H. G., Thiele, H., Nürnberg, P., Höhne, W., Crow, Y. J., Feigenbaum, A., & Hennekam, R. C. (2015). A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome. American journal of human genetics, 96(2), 275-282. https://doi.org/10.1016/j.ajhg.2014.12.014

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title = "A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome",

abstract = "Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutieres syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption",

author = "Frank Rutsch and Mary Macdougall and Changming Lu and Insa Buers and Olga Mamaeva and Yvonne Nitschke and Rice, {Gillian I.} and Heidi Erlandsen and Kehl, {Hans Gerd} and Holger Thiele and Peter N{\"u}rnberg and Wolfgang H{\"o}hne and Crow, {Yanick J.} and Annette Feigenbaum and Hennekam, {Raoul C.}",

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AU - Rutsch, Frank

AU - Macdougall, Mary

AU - Lu, Changming

AU - Buers, Insa

AU - Mamaeva, Olga

AU - Nitschke, Yvonne

AU - Rice, Gillian I.

AU - Erlandsen, Heidi

AU - Kehl, Hans Gerd

AU - Thiele, Holger

AU - Nürnberg, Peter

AU - Höhne, Wolfgang

AU - Crow, Yanick J.

AU - Feigenbaum, Annette

AU - Hennekam, Raoul C.

PY - 2015

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N2 - Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutieres syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption

AB - Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutieres syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption

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