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Updated: Jul 7, 2025

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A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of

Erica L Harris1, Vincent Roy2, Martin Montagne2

  • 1Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

American Journal of Human Genetics
|December 23, 2023
PubMed

Insights

A novel Myc-associated factor X (MAX) gene variant causes macrocephaly by increasing cyclin D2 (CCND2) transcription. This MAX mutation enhances c-Myc activity, suggesting a therapeutic target for related disorders.

Area of Science:

  • Genetics
  • Molecular Biology
  • Developmental Biology

Background:

  • Macrocephaly disorders are often linked to Cyclin D2 (CCND2) stabilization.
  • Mutations in CCND2 or the PI3K-AKT pathway are common causes.

Purpose of the Study:

  • Investigate the genetic basis of macrocephaly in three individuals with overlapping phenotypes.
  • Characterize a novel de novo variant in the Myc-associated factor X (MAX) gene.

Main Methods:

  • Genetic sequencing to identify variants.
  • In vitro analysis of the MAX b-HLH-LZ domain protein function.
  • Assessment of c-Myc transcriptional activity.

Main Results:

  • Identified a recurrent de novo c.179G>A (p.Arg60Gln) variant in MAX in three individuals.
  • The MAX Arg60Gln mutation increases CCND2 transcription but not its stabilization.
  • The MAX Arg60Gln variant exhibits reduced binding affinity, enhancing c-Myc heterodimerization and transcriptional activity.

Conclusions:

  • The MAX Arg60Gln variant contributes to macrocephaly through increased c-Myc-driven transcription.
  • Omomyc-CPP, a c-Myc inhibitor, presents a potential therapeutic strategy for individuals with this MAX mutation.
Keywords:
CCND2MAXMYCb-HLH-LZmacrocephalypolydactyly

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