A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. J Biol Chem 2017 Mar 03;292(9):3866-3876
Date
01/07/2017Pubmed ID
28057753Pubmed Central ID
PMC5339767DOI
10.1074/jbc.M116.770545Scopus ID
2-s2.0-85014566714 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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.
Author List
Blackburn PR, Tischer A, Zimmermann MT, Kemppainen JL, Sastry S, Knight Johnson AE, Cousin MA, Boczek NJ, Oliver G, Misra VK, Gavrilova RH, Lomberk G, Auton M, Urrutia R, Klee EWAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinMichael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Amino Acid MotifsAnkyrin Repeat
Autism Spectrum Disorder
Child, Preschool
Chromosome Deletion
Chromosomes, Human, Pair 9
Craniofacial Abnormalities
Female
Genetic Variation
Genomics
Heart Defects, Congenital
Histone-Lysine N-Methyltransferase
Humans
Intellectual Disability
Molecular Dynamics Simulation
Mutation, Missense
Phenotype
Protein Folding
Spectrometry, Fluorescence