Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Shannon Marchegiani; Taylor Davis; Federico Tessadori; Gijs van Haaften; Francesco Brancati; Alexander Hoischen; Haigen Huang; Elise Valkanas; Barbara Pusey; Denny Schanze; Hanka Venselaar; Anneke T Vulto-van Silfhout; Lynne A Wolfe; Cynthia J Tifft; Patricia M Zerfas; Giovanna Zambruno; Ariana Kariminejad; Farahnaz Sabbagh-Kermani; Janice Lee; Maria G Tsokos; Chyi-Chia R Lee; Victor Ferraz; Eduarda Morgana da Silva; Cathy A Stevens; Nathalie Roche; Oliver Bartsch; Peter Farndon; Eva Bermejo-Sanchez; Brian P Brooks; Valerie Maduro; Bruno Dallapiccola; Feliciano J Ramos; Hon-Yin Brian Chung; Cédric Le Caignec; Fabiana Martins; Witold K Jacyk; Laura Mazzanti; Han G Brunner; Jeroen Bakkers; Shuo Lin; May Christine V Malicdan; Cornelius F Boerkoel; William A Gahl; Bert B A de Vries; Mieke M van Haelst; Martin Zenker; Thomas C Markello

doi:10.1016/j.ajhg.2015.05.017

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Shannon Marchegiani, Taylor Davis, Federico Tessadori, Gijs van Haaften, Francesco Brancati, Alexander Hoischen, Haigen Huang, Elise Valkanas, Barbara Pusey, Denny Schanze, Hanka Venselaar, Anneke T Vulto-van Silfhout, Lynne A Wolfe, Cynthia J Tifft, Patricia M Zerfas, Giovanna Zambruno, Ariana Kariminejad, Farahnaz Sabbagh-Kermani, Janice Lee, Maria G TsokosChyi-Chia R Lee, Victor Ferraz, Eduarda Morgana da Silva, Cathy A Stevens, Nathalie Roche, Oliver Bartsch, Peter Farndon, Eva Bermejo-Sanchez, Brian P Brooks, Valerie Maduro, Bruno Dallapiccola, Feliciano J Ramos, Hon-Yin Brian Chung, Cédric Le Caignec, Fabiana Martins, Witold K Jacyk, Laura Mazzanti, Han G Brunner, Jeroen Bakkers, Shuo Lin, May Christine V Malicdan, Cornelius F Boerkoel, William A Gahl, Bert B A de Vries, Mieke M van Haelst, Martin Zenker, Thomas C Markello

Hubrecht Institute

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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.

Originele taal-2	Engels
Pagina's (van-tot)	99-110
Aantal pagina's	12
Tijdschrift	American Journal of Human Genetics
Volume	97
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1016/j.ajhg.2015.05.017
Status	Gepubliceerd - 02 jul. 2015

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10.1016/j.ajhg.2015.05.017

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Marchegiani, S., Davis, T., Tessadori, F., van Haaften, G., Brancati, F., Hoischen, A., Huang, H., Valkanas, E., Pusey, B., Schanze, D., Venselaar, H., Vulto-van Silfhout, A. T., Wolfe, L. A., Tifft, C. J., Zerfas, P. M., Zambruno, G., Kariminejad, A., Sabbagh-Kermani, F., Lee, J., ... Markello, T. C. (2015). Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. American Journal of Human Genetics, 97(1), 99-110. https://doi.org/10.1016/j.ajhg.2015.05.017

@article{cb9471bc714f4698b3f26dccb1957e5a,

title = "Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes",

abstract = "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.",

author = "Shannon Marchegiani and Taylor Davis and Federico Tessadori and {van Haaften}, Gijs and Francesco Brancati and Alexander Hoischen and Haigen Huang and Elise Valkanas and Barbara Pusey and Denny Schanze and Hanka Venselaar and {Vulto-van Silfhout}, {Anneke T} and Wolfe, {Lynne A} and Tifft, {Cynthia J} and Zerfas, {Patricia M} and Giovanna Zambruno and Ariana Kariminejad and Farahnaz Sabbagh-Kermani and Janice Lee and Tsokos, {Maria G} and Lee, {Chyi-Chia R} and Victor Ferraz and {da Silva}, {Eduarda Morgana} and Stevens, {Cathy A} and Nathalie Roche and Oliver Bartsch and Peter Farndon and Eva Bermejo-Sanchez and Brooks, {Brian P} and Valerie Maduro and Bruno Dallapiccola and Ramos, {Feliciano J} and Chung, {Hon-Yin Brian} and {Le Caignec}, C{\'e}dric and Fabiana Martins and Jacyk, {Witold K} and Laura Mazzanti and Brunner, {Han G} and Jeroen Bakkers and Shuo Lin and Malicdan, {May Christine V} and Boerkoel, {Cornelius F} and Gahl, {William A} and {de Vries}, {Bert B A} and {van Haelst}, {Mieke M} and Martin Zenker and Markello, {Thomas C}",

year = "2015",

month = jul,

day = "2",

doi = "10.1016/j.ajhg.2015.05.017",

language = "English",

volume = "97",

pages = "99--110",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

Marchegiani, S, Davis, T, Tessadori, F, van Haaften, G, Brancati, F, Hoischen, A, Huang, H, Valkanas, E, Pusey, B, Schanze, D, Venselaar, H, Vulto-van Silfhout, AT, Wolfe, LA, Tifft, CJ, Zerfas, PM, Zambruno, G, Kariminejad, A, Sabbagh-Kermani, F, Lee, J, Tsokos, MG, Lee, C-CR, Ferraz, V, da Silva, EM, Stevens, CA, Roche, N, Bartsch, O, Farndon, P, Bermejo-Sanchez, E, Brooks, BP, Maduro, V, Dallapiccola, B, Ramos, FJ, Chung, H-YB, Le Caignec, C, Martins, F, Jacyk, WK, Mazzanti, L, Brunner, HG, Bakkers, J, Lin, S, Malicdan, MCV, Boerkoel, CF, Gahl, WA, de Vries, BBA, van Haelst, MM, Zenker, M & Markello, TC 2015, 'Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes', American Journal of Human Genetics, vol. 97, nr. 1, blz. 99-110. https://doi.org/10.1016/j.ajhg.2015.05.017

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. / Marchegiani, Shannon; Davis, Taylor; Tessadori, Federico et al.
In: American Journal of Human Genetics, Vol. 97, Nr. 1, 02.07.2015, blz. 99-110.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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

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.

U2 - 10.1016/j.ajhg.2015.05.017

DO - 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 -

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

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