TY - JOUR
T1 - Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes
AU - Marchegiani, Shannon
AU - Davis, Taylor
AU - Tessadori, Federico
AU - van Haaften, Gijs
AU - Brancati, Francesco
AU - Hoischen, Alexander
AU - Huang, Haigen
AU - Valkanas, Elise
AU - Pusey, Barbara
AU - Schanze, Denny
AU - Venselaar, Hanka
AU - Vulto-van Silfhout, Anneke T
AU - Wolfe, Lynne A
AU - Tifft, Cynthia J
AU - Zerfas, Patricia M
AU - Zambruno, Giovanna
AU - Kariminejad, Ariana
AU - Sabbagh-Kermani, Farahnaz
AU - Lee, Janice
AU - Tsokos, Maria G
AU - Lee, Chyi-Chia R
AU - Ferraz, Victor
AU - da Silva, Eduarda Morgana
AU - Stevens, Cathy A
AU - Roche, Nathalie
AU - Bartsch, Oliver
AU - Farndon, Peter
AU - Bermejo-Sanchez, Eva
AU - Brooks, Brian P
AU - Maduro, Valerie
AU - Dallapiccola, Bruno
AU - Ramos, Feliciano J
AU - Chung, Hon-Yin Brian
AU - Le Caignec, Cédric
AU - Martins, Fabiana
AU - Jacyk, Witold K
AU - Mazzanti, Laura
AU - Brunner, Han G
AU - Bakkers, Jeroen
AU - Lin, Shuo
AU - Malicdan, May Christine V
AU - Boerkoel, Cornelius F
AU - Gahl, William A
AU - de Vries, Bert B A
AU - van Haelst, Mieke M
AU - Zenker, Martin
AU - Markello, Thomas C
N1 - Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2015/7/2
Y1 - 2015/7/2
N2 - Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
AB - Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
KW - Abnormalities, Multiple/genetics
KW - Amino Acid Sequence
KW - Animals
KW - Base Sequence
KW - Chromatin Immunoprecipitation
KW - Exome/genetics
KW - Eye Abnormalities/genetics
KW - Eyelid Diseases/genetics
KW - HeLa Cells
KW - Hirsutism/genetics
KW - Humans
KW - Hypertelorism/genetics
KW - Hypertrichosis/genetics
KW - Macrostomia/genetics
KW - Microscopy, Electron
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Mutation, Missense/genetics
KW - Phenotype
KW - Protein Conformation
KW - Repressor Proteins/chemistry
KW - Sequence Analysis, DNA
KW - Skin Abnormalities/genetics
KW - Twist-Related Protein 1/chemistry
KW - Zebrafish
U2 - https://doi.org/10.1016/j.ajhg.2015.05.017
DO - https://doi.org/10.1016/j.ajhg.2015.05.017
M3 - Article
C2 - 26119818
SN - 0002-9297
VL - 97
SP - 99
EP - 110
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -