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A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding

Kleefstra syndrome (KS) (Mendelian Inheritance in Man (MIM) no. 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disa...

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Autores principales: Blackburn, Patrick R., Tischer, Alexander, Zimmermann, Michael T., Kemppainen, Jennifer L., Sastry, Sujatha, Knight Johnson, Amy E., Cousin, Margot A., Boczek, Nicole J., Oliver, Gavin, Misra, Vinod K., Gavrilova, Ralitza H., Lomberk, Gwen, Auton, Matthew, Urrutia, Raul, Klee, Eric W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339767/
https://www.ncbi.nlm.nih.gov/pubmed/28057753
http://dx.doi.org/10.1074/jbc.M116.770545
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author Blackburn, Patrick R.
Tischer, Alexander
Zimmermann, Michael T.
Kemppainen, Jennifer L.
Sastry, Sujatha
Knight Johnson, Amy E.
Cousin, Margot A.
Boczek, Nicole J.
Oliver, Gavin
Misra, Vinod K.
Gavrilova, Ralitza H.
Lomberk, Gwen
Auton, Matthew
Urrutia, Raul
Klee, Eric W.
author_facet Blackburn, Patrick R.
Tischer, Alexander
Zimmermann, Michael T.
Kemppainen, Jennifer L.
Sastry, Sujatha
Knight Johnson, Amy E.
Cousin, Margot A.
Boczek, Nicole J.
Oliver, Gavin
Misra, Vinod K.
Gavrilova, Ralitza H.
Lomberk, Gwen
Auton, Matthew
Urrutia, Raul
Klee, Eric W.
author_sort Blackburn, Patrick R.
collection PubMed
description Kleefstra syndrome (KS) (Mendelian Inheritance in Man (MIM) no. 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and dysmorphic facial features with hypertelorism, synophrys, macroglossia, protruding tongue, and prognathism. Only a few cases of de novo missense mutations in EHMT1 giving rise to KS have been described. However, some EHMT1 variants have been described in individuals presenting with autism spectrum disorder or mild intellectual disability, suggesting that the phenotypic spectrum resulting from EHMT1 alterations may be quite broad. In this report, we describe two unrelated patients with complex medical histories consistent with KS in whom next generation sequencing identified the same novel c.2426C>T (p.P809L) missense variant in EHMT1. To examine the functional significance of this novel variant, we performed molecular dynamics simulations of the wild type and p.P809L variant, which predicted that the latter would have a propensity to misfold, leading to abnormal histone mark binding. Recombinant EHMT1 p.P809L was also studied using far UV circular dichroism spectroscopy and intrinsic protein fluorescence. These functional studies confirmed the model-based hypotheses and provided evidence for protein misfolding and aberrant target recognition as the underlying pathogenic mechanism for this novel KS-associated variant. This is the first report to suggest that missense variants in EHMT1 that lead to protein misfolding and disrupted histone mark binding can lead to KS.
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spelling pubmed-53397672017-03-23 A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding Blackburn, Patrick R. Tischer, Alexander Zimmermann, Michael T. Kemppainen, Jennifer L. Sastry, Sujatha Knight Johnson, Amy E. Cousin, Margot A. Boczek, Nicole J. Oliver, Gavin Misra, Vinod K. Gavrilova, Ralitza H. Lomberk, Gwen Auton, Matthew Urrutia, Raul Klee, Eric W. J Biol Chem Molecular Bases of Disease Kleefstra syndrome (KS) (Mendelian Inheritance in Man (MIM) no. 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and dysmorphic facial features with hypertelorism, synophrys, macroglossia, protruding tongue, and prognathism. Only a few cases of de novo missense mutations in EHMT1 giving rise to KS have been described. However, some EHMT1 variants have been described in individuals presenting with autism spectrum disorder or mild intellectual disability, suggesting that the phenotypic spectrum resulting from EHMT1 alterations may be quite broad. In this report, we describe two unrelated patients with complex medical histories consistent with KS in whom next generation sequencing identified the same novel c.2426C>T (p.P809L) missense variant in EHMT1. To examine the functional significance of this novel variant, we performed molecular dynamics simulations of the wild type and p.P809L variant, which predicted that the latter would have a propensity to misfold, leading to abnormal histone mark binding. Recombinant EHMT1 p.P809L was also studied using far UV circular dichroism spectroscopy and intrinsic protein fluorescence. These functional studies confirmed the model-based hypotheses and provided evidence for protein misfolding and aberrant target recognition as the underlying pathogenic mechanism for this novel KS-associated variant. This is the first report to suggest that missense variants in EHMT1 that lead to protein misfolding and disrupted histone mark binding can lead to KS. American Society for Biochemistry and Molecular Biology 2017-03-03 2017-01-05 /pmc/articles/PMC5339767/ /pubmed/28057753 http://dx.doi.org/10.1074/jbc.M116.770545 Text en © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Molecular Bases of Disease
Blackburn, Patrick R.
Tischer, Alexander
Zimmermann, Michael T.
Kemppainen, Jennifer L.
Sastry, Sujatha
Knight Johnson, Amy E.
Cousin, Margot A.
Boczek, Nicole J.
Oliver, Gavin
Misra, Vinod K.
Gavrilova, Ralitza H.
Lomberk, Gwen
Auton, Matthew
Urrutia, Raul
Klee, Eric W.
A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title_full A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title_fullStr A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title_full_unstemmed A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title_short A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding
title_sort novel kleefstra syndrome-associated variant that affects the conserved tplx motif within the ankyrin repeat of ehmt1 leads to abnormal protein folding
topic Molecular Bases of Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339767/
https://www.ncbi.nlm.nih.gov/pubmed/28057753
http://dx.doi.org/10.1074/jbc.M116.770545
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