Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Marcello Niceta, Emilia Stellacci, Karen W. Gripp, Giuseppe Zampino, Maria Kousi, Massimiliano Anselmi, Alice Traversa, Andrea Ciolfi, Alessandro Ciolfi, Deborah Stabley, Alessandro Bruselles, Viviana Caputo, Serena Cecchetti, Sabrina Prudente, Maria T. Fiorenza, Carla Boitani, Nicole Philip, Dmitriy Niyazov, Chiara Leoni, Takaya NakaneKim Keppler-Noreuil, Stephen R. Braddock, Gabriele Gillessen-Kaesbach, Antonio Palleschi, Philippe M. Campeau, Brendan H.L. Lee, Celio Pouponnot, Lorenzo Stella, Gianfranco Bocchinfuso, Nicholas Katsanis, Katia Sol-Church, Marco Tartaglia

Research output: Contribution to journalArticle

63 Citations (Scopus)


Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development.
Original languageEnglish
Pages (from-to)816-825
Number of pages10
JournalAmerican Journal of Human Genetics
Publication statusPublished - 2015


  • Cataract
  • Deafness
  • Down Syndrome
  • Glycogen Synthase Kinase 3
  • Humans
  • Intellectual Disability
  • Mutation
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-maf
  • Seizures


Dive into the research topics of 'Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies'. Together they form a unique fingerprint.

Cite this