Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Marlinde L. Van Den Boogaard; Richard J.L.F. Lemmers; Judit Balog; Mariëlle Wohlgemuth; Mari Auranen; Satomi Mitsuhashi; Patrick J. Van Der Vliet; Kirsten R. Straasheijm; Rob F.P. Van Den Akker; Marjolein Kriek; Marlies E.Y. Laurense-Bik; Vered Raz; Monique M. Van Ostaijen-Ten Dam; Kerstin B.M. Hansson; Elly L. Van Der Kooi; Sari Kiuru-Enari; Bjarne Udd; Maarten J.D. Van Tol; Ichizo Nishino; Rabi Tawil; Stephen J. Tapscott; Baziel G.M. Van Engelen; Silvère M. Van Der Maarel

doi:10.1016/j.ajhg.2016.03.013

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Marlinde L. Van Den Boogaard, Richard J.L.F. Lemmers, Judit Balog, Mariëlle Wohlgemuth, Mari Auranen, Satomi Mitsuhashi, Patrick J. Van Der Vliet, Kirsten R. Straasheijm, Rob F.P. Van Den Akker, Marjolein Kriek, Marlies E.Y. Laurense-Bik, Vered Raz, Monique M. Van Ostaijen-Ten Dam, Kerstin B.M. Hansson, Elly L. Van Der Kooi, Sari Kiuru-Enari, Bjarne Udd, Maarten J.D. Van Tol, Ichizo Nishino, Rabi TawilStephen J. Tapscott, Baziel G.M. Van Engelen, Silvère M. Van Der Maarel

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Abstract

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

Original language	English
Pages (from-to)	1020-1029
Number of pages	10
Journal	American Journal of Human Genetics
Volume	98
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2016.03.013
Publication status	Published - 5 May 2016
Externally published	Yes

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Van Den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., Van Der Vliet, P. J., Straasheijm, K. R., Van Den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., Van Ostaijen-Ten Dam, M. M., Hansson, K. B. M., Van Der Kooi, E. L., Kiuru-Enari, S., Udd, B., Van Tol, M. J. D., Nishino, I., ... Van Der Maarel, S. M. (2016). Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. American Journal of Human Genetics, 98(5), 1020-1029. https://doi.org/10.1016/j.ajhg.2016.03.013

@article{e4d19375f3de4c87a13d6ae437046436,

title = "Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy",

abstract = "Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.",

author = "{Van Den Boogaard}, {Marlinde L.} and Lemmers, {Richard J.L.F.} and Judit Balog and Mari{\"e}lle Wohlgemuth and Mari Auranen and Satomi Mitsuhashi and {Van Der Vliet}, {Patrick J.} and Straasheijm, {Kirsten R.} and {Van Den Akker}, {Rob F.P.} and Marjolein Kriek and Laurense-Bik, {Marlies E.Y.} and Vered Raz and {Van Ostaijen-Ten Dam}, {Monique M.} and Hansson, {Kerstin B.M.} and {Van Der Kooi}, {Elly L.} and Sari Kiuru-Enari and Bjarne Udd and {Van Tol}, {Maarten J.D.} and Ichizo Nishino and Rabi Tawil and Tapscott, {Stephen J.} and {Van Engelen}, {Baziel G.M.} and {Van Der Maarel}, {Silv{\`e}re M.}",

year = "2016",

month = may,

day = "5",

doi = "10.1016/j.ajhg.2016.03.013",

language = "English",

volume = "98",

pages = "1020--1029",

journal = "American Journal of Human Genetics",

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Van Den Boogaard, ML, Lemmers, RJLF, Balog, J, Wohlgemuth, M, Auranen, M, Mitsuhashi, S, Van Der Vliet, PJ, Straasheijm, KR, Van Den Akker, RFP, Kriek, M, Laurense-Bik, MEY, Raz, V, Van Ostaijen-Ten Dam, MM, Hansson, KBM, Van Der Kooi, EL, Kiuru-Enari, S, Udd, B, Van Tol, MJD, Nishino, I, Tawil, R, Tapscott, SJ, Van Engelen, BGM & Van Der Maarel, SM 2016, 'Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy', American Journal of Human Genetics, vol. 98, no. 5, pp. 1020-1029. https://doi.org/10.1016/j.ajhg.2016.03.013

TY - JOUR

T1 - Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

AU - Van Den Boogaard, Marlinde L.

AU - Lemmers, Richard J.L.F.

AU - Balog, Judit

AU - Wohlgemuth, Mariëlle

AU - Auranen, Mari

AU - Mitsuhashi, Satomi

AU - Van Der Vliet, Patrick J.

AU - Straasheijm, Kirsten R.

AU - Van Den Akker, Rob F.P.

AU - Kriek, Marjolein

AU - Laurense-Bik, Marlies E.Y.

AU - Raz, Vered

AU - Van Ostaijen-Ten Dam, Monique M.

AU - Hansson, Kerstin B.M.

AU - Van Der Kooi, Elly L.

AU - Kiuru-Enari, Sari

AU - Udd, Bjarne

AU - Van Tol, Maarten J.D.

AU - Nishino, Ichizo

AU - Tawil, Rabi

AU - Tapscott, Stephen J.

AU - Van Engelen, Baziel G.M.

AU - Van Der Maarel, Silvère M.

PY - 2016/5/5

Y1 - 2016/5/5

N2 - Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

AB - Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

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U2 - 10.1016/j.ajhg.2016.03.013

DO - 10.1016/j.ajhg.2016.03.013

M3 - Article

C2 - 27153398

AN - SCOPUS:84968791300

SN - 0002-9297

VL - 98

SP - 1020

EP - 1029

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Abstract

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