De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

M. Felicia Basilicata; Ange Line Bruel; Giuseppe Semplicio; Claudia Isabelle Keller Valsecchi; Tuğçe Aktaş; Yannis Duffourd; Tobias Rumpf; Jenny Morton; Iben Bache; Witold G. Szymanski; Christian Gilissen; Olivier Vanakker; Katrin Õunap; Gerhard Mittler; Ineke van der Burgt; Salima El Chehadeh; Megan T. Cho; Rolph Pfundt; Tiong Yang Tan; Maria Kirchhoff; Björn Menten; Sarah Vergult; Kristin Lindstrom; André Reis; Diana S. Johnson; Alan Fryer; Victoria McKay; Richard B. Fisher; Christel Thauvin-Robinet; David Francis; Tony Roscioli; Sander Pajusalu; Kelly Radtke; Jaya Ganesh; Han G. Brunner; Meredith Wilson; Laurence Faivre; Vera M. Kalscheuer; Julien Thevenon; Asifa Akhtar; DDD Study

doi:10.1038/s41588-018-0220-y

De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

M. Felicia Basilicata, Ange Line Bruel, Giuseppe Semplicio, Claudia Isabelle Keller Valsecchi, Tuğçe Aktaş, Yannis Duffourd, Tobias Rumpf, Jenny Morton, Iben Bache, Witold G. Szymanski, Christian Gilissen, Olivier Vanakker, Katrin Õunap, Gerhard Mittler, Ineke van der Burgt, Salima El Chehadeh, Megan T. Cho, Rolph Pfundt, Tiong Yang Tan, Maria KirchhoffBjörn Menten, Sarah Vergult, Kristin Lindstrom, André Reis, Diana S. Johnson, Alan Fryer, Victoria McKay, Richard B. Fisher, Christel Thauvin-Robinet, David Francis, Tony Roscioli, Sander Pajusalu, Kelly Radtke, Jaya Ganesh, Han G. Brunner, Meredith Wilson, Laurence Faivre, Vera M. Kalscheuer, Julien Thevenon, Asifa Akhtar^*, DDD Study

^*Corresponding author for this work

Medical Genetics Program

12 Citations (Scopus)

Abstract

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

Original language	English
Journal	Nature Genetics
Volume	50
Issue number	10
Pages (from-to)	1442-1451
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0220-y
Publication status	Published - 2018

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Basilicata, M. F., Bruel, A. L., Semplicio, G., Valsecchi, C. I. K., Aktaş, T., Duffourd, Y., Rumpf, T., Morton, J., Bache, I., Szymanski, W. G., Gilissen, C., Vanakker, O., Õunap, K., Mittler, G., van der Burgt, I., El Chehadeh, S., Cho, M. T., Pfundt, R., Tan, T. Y., ... DDD Study (2018). De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nature Genetics, 50(10), 1442-1451. https://doi.org/10.1038/s41588-018-0220-y

Basilicata, MF, Bruel, AL, Semplicio, G, Valsecchi, CIK, Aktaş, T, Duffourd, Y, Rumpf, T, Morton, J, Bache, I, Szymanski, WG, Gilissen, C, Vanakker, O, Õunap, K, Mittler, G, van der Burgt, I, El Chehadeh, S, Cho, MT, Pfundt, R, Tan, TY, Kirchhoff, M, Menten, B, Vergult, S, Lindstrom, K, Reis, A, Johnson, DS, Fryer, A, McKay, V, Fisher, RB, Thauvin-Robinet, C, Francis, D, Roscioli, T, Pajusalu, S, Radtke, K, Ganesh, J, Brunner, HG, Wilson, M, Faivre, L, Kalscheuer, VM, Thevenon, J, Akhtar, A & DDD Study 2018, 'De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation', Nature Genetics, vol. 50, no. 10, pp. 1442-1451. https://doi.org/10.1038/s41588-018-0220-y

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title = "De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation",

abstract = "The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.",

author = "Basilicata, {M. Felicia} and Bruel, {Ange Line} and Giuseppe Semplicio and Valsecchi, {Claudia Isabelle Keller} and Tuğ{\c c}e Akta{\c s} and Yannis Duffourd and Tobias Rumpf and Jenny Morton and Iben Bache and Szymanski, {Witold G.} and Christian Gilissen and Olivier Vanakker and Katrin {\~O}unap and Gerhard Mittler and {van der Burgt}, Ineke and {El Chehadeh}, Salima and Cho, {Megan T.} and Rolph Pfundt and Tan, {Tiong Yang} and Maria Kirchhoff and Bj{\"o}rn Menten and Sarah Vergult and Kristin Lindstrom and Andr{\'e} Reis and Johnson, {Diana S.} and Alan Fryer and Victoria McKay and Fisher, {Richard B.} and Christel Thauvin-Robinet and David Francis and Tony Roscioli and Sander Pajusalu and Kelly Radtke and Jaya Ganesh and Brunner, {Han G.} and Meredith Wilson and Laurence Faivre and Kalscheuer, {Vera M.} and Julien Thevenon and Asifa Akhtar and {DDD Study}",

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doi = "10.1038/s41588-018-0220-y",

language = "English",

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T1 - De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

AU - Basilicata, M. Felicia

AU - Bruel, Ange Line

AU - Semplicio, Giuseppe

AU - Valsecchi, Claudia Isabelle Keller

AU - Aktaş, Tuğçe

AU - Duffourd, Yannis

AU - Rumpf, Tobias

AU - Morton, Jenny

AU - Bache, Iben

AU - Szymanski, Witold G.

AU - Gilissen, Christian

AU - Vanakker, Olivier

AU - Õunap, Katrin

AU - Mittler, Gerhard

AU - van der Burgt, Ineke

AU - El Chehadeh, Salima

AU - Cho, Megan T.

AU - Pfundt, Rolph

AU - Tan, Tiong Yang

AU - Kirchhoff, Maria

AU - Menten, Björn

AU - Vergult, Sarah

AU - Lindstrom, Kristin

AU - Reis, André

AU - Johnson, Diana S.

AU - Fryer, Alan

AU - McKay, Victoria

AU - Fisher, Richard B.

AU - Thauvin-Robinet, Christel

AU - Francis, David

AU - Roscioli, Tony

AU - Pajusalu, Sander

AU - Radtke, Kelly

AU - Ganesh, Jaya

AU - Brunner, Han G.

AU - Wilson, Meredith

AU - Faivre, Laurence

AU - Kalscheuer, Vera M.

AU - Thevenon, Julien

AU - Akhtar, Asifa

AU - DDD Study

PY - 2018

Y1 - 2018

N2 - The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

AB - The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

U2 - 10.1038/s41588-018-0220-y

DO - 10.1038/s41588-018-0220-y

M3 - Journal article

C2 - 30224647

AN - SCOPUS:85053659385

SN - 1061-4036

VL - 50

SP - 1442

EP - 1451

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Abstract

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