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

• Published in: American journal of human genetics 2024-01, Vol.111 (1), p.119-132
• Main Authors: Harris, Erica L., Roy, Vincent, Montagne, Martin, Rose, Ailsa M.S., Livesey, Helen, Reijnders, Margot R.F., Hobson, Emma, Sansbury, Francis H., Willemsen, Marjolein H., Pfundt, Rolph, Warren, Daniel, Long, Vernon, Carr, Ian M., Brunner, Han G., Sheridan, Eamonn G., Firth, Helen V., Lavigne, Pierre, Poulter, James A.
• Format: Article
• Language: English
• Subjects: b-HLH-LZ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; CCND2; Dimerization; Humans; macrocephaly; MAX; Megalencephaly - genetics; MYC; Phosphatidylinositol 3-Kinases - metabolism; polydactyly; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2023.11.010

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. Harris et al. describe three individuals with overlapping macrocephaly-associated phenotypes carrying a recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). MAXArg60Gln binds its target E-box sequence with a lower affinity, meaning more efficient heterodimerization with c-Myc and dysregulated transcriptional activity. c-Myc inhibitors provide a possible therapeutic option for individuals carrying this variant.