A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

Erica L. Harris; Vincent Roy; Martin Montagne; Ailsa M.S. Rose; Helen Livesey; Margot R.F. Reijnders; Emma Hobson; Francis H. Sansbury; Marjolein H. Willemsen; Rolph Pfundt; Daniel Warren; Vernon Long; Ian M. Carr; Han G. Brunner; Eamonn G. Sheridan; Helen V. Firth; Pierre Lavigne; James A. Poulter

doi:10.1016/j.ajhg.2023.11.010

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

Erica L. Harris
, Vincent Roy
, Martin Montagne
, Ailsa M.S. Rose
, Helen Livesey
, Margot R.F. Reijnders
, Emma Hobson
, Francis H. Sansbury
, Marjolein H. Willemsen
, Rolph Pfundt
, Daniel Warren
, Vernon Long
, Ian M. Carr
, Han G. Brunner
, Eamonn G. Sheridan
, Helen V. Firth
, Pierre Lavigne^*
, James A. Poulter^*

^*Corresponding author for this work

University of Leeds, School of Medicine
PROTÉO et Institut de Pharmacologie de Sherbrooke. University of Sherbrooke
Leeds Teaching Hospitals NHS Trust
Cardiff & Vale University Health Board
Erasmus University Rotterdam
Radboud University Medical Center
Addenbrooke's Hospital
Wellcome Sanger Institute

Research output: Contribution to journal › Article › Academic › peer-review

6 Citations (Scopus)

8 Downloads (Pure)

Abstract

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX^Arg60Gln (Max^∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX^Arg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Original language	English
Pages (from-to)	119-132
Number of pages	14
Journal	American Journal of Human Genetics
Volume	111
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2023.11.010
Publication status	Published - 4 Jan 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Acknowledgments:
The authors would like to thank the affected individuals and their families.

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1-s2.0-S0002929723004287-mainFinal published version, 4.97 MBLicence: CC BY

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Harris, E. L., Roy, V., Montagne, M., Rose, A. M. S., Livesey, H., Reijnders, M. R. F., Hobson, E., Sansbury, F. H., Willemsen, M. H., Pfundt, R., Warren, D., Long, V., Carr, I. M., Brunner, H. G., Sheridan, E. G., Firth, H. V., Lavigne, P., & Poulter, J. A. (2024). A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes. American Journal of Human Genetics, 111(1), 119-132. https://doi.org/10.1016/j.ajhg.2023.11.010

@article{ea8c539eaa784ac087a28196e9b33259,

title = "A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes",

abstract = "Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.",

author = "Harris, \{Erica L.\} and Vincent Roy and Martin Montagne and Rose, \{Ailsa M.S.\} and Helen Livesey and Reijnders, \{Margot R.F.\} and Emma Hobson and Sansbury, \{Francis H.\} and Willemsen, \{Marjolein H.\} and Rolph Pfundt and Daniel Warren and Vernon Long and Carr, \{Ian M.\} and Brunner, \{Han G.\} and Sheridan, \{Eamonn G.\} and Firth, \{Helen V.\} and Pierre Lavigne and Poulter, \{James A.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors Acknowledgments: The authors would like to thank the affected individuals and their families.",

year = "2024",

month = jan,

day = "4",

doi = "10.1016/j.ajhg.2023.11.010",

language = "English",

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Harris, EL, Roy, V, Montagne, M, Rose, AMS, Livesey, H, Reijnders, MRF, Hobson, E, Sansbury, FH, Willemsen, MH, Pfundt, R, Warren, D, Long, V, Carr, IM, Brunner, HG, Sheridan, EG, Firth, HV, Lavigne, P & Poulter, JA 2024, 'A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes', American Journal of Human Genetics, vol. 111, no. 1, pp. 119-132. https://doi.org/10.1016/j.ajhg.2023.11.010

TY - JOUR

T1 - A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

AU - Harris, Erica L.

AU - Roy, Vincent

AU - Montagne, Martin

AU - Rose, Ailsa M.S.

AU - Livesey, Helen

AU - Reijnders, Margot R.F.

AU - Hobson, Emma

AU - Sansbury, Francis H.

AU - Willemsen, Marjolein H.

AU - Pfundt, Rolph

AU - Warren, Daniel

AU - Long, Vernon

AU - Carr, Ian M.

AU - Brunner, Han G.

AU - Sheridan, Eamonn G.

AU - Firth, Helen V.

AU - Lavigne, Pierre

AU - Poulter, James A.

PY - 2024/1/4

Y1 - 2024/1/4

N2 - Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

AB - Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

UR - https://www.scopus.com/pages/publications/85181257911

U2 - 10.1016/j.ajhg.2023.11.010

DO - 10.1016/j.ajhg.2023.11.010

M3 - Article

C2 - 38141607

AN - SCOPUS:85181257911

SN - 0002-9297

VL - 111

SP - 119

EP - 132

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

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