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

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies / E. Stellacci, M. Niceta; Gripp, K. W.; Zampino, G.; Kousi, M.; Manselmi, M. Anselmi; Traversa, A.; Ciolfi, A.; Stabley, D.; Bruselles, A.; Caputo, V.; Scecchetti, S. Cecchetti; Prudente, S.; Fiorenza, M. T.; Boitani, C.; Philip, N.; Dniyazov, D. Niyazov; Leoni, C.; Nakane, T.; Keppler-Noreuil, K.; Braddock, S. R.; Gillessen-Kaesbach, G.; Palleschi, A.; Campeau, P. M.; Lee, B. H. L.; Pouponnot, C.; Stella, L.; Gbocchinfuso, G. Bocchinfuso; Nkatsanis, N. Katsanis; KSol-Church, K. Sol-Church. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 96:5(2015), pp. 816-825. [10.1016/j.ajhg.2015.03.001]

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

A. Traversa;Caputo, V.;Fiorenza, M. T.;Boitani, C.;Stella, L.;
2015

Abstract

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
2015
MAF; mutations; developmental defects; aimé-gripp syndrome
01 Pubblicazione su rivista::01i Case report
Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies / E. Stellacci, M. Niceta; Gripp, K. W.; Zampino, G.; Kousi, M.; Manselmi, M. Anselmi; Traversa, A.; Ciolfi, A.; Stabley, D.; Bruselles, A.; Caputo, V.; Scecchetti, S. Cecchetti; Prudente, S.; Fiorenza, M. T.; Boitani, C.; Philip, N.; Dniyazov, D. Niyazov; Leoni, C.; Nakane, T.; Keppler-Noreuil, K.; Braddock, S. R.; Gillessen-Kaesbach, G.; Palleschi, A.; Campeau, P. M.; Lee, B. H. L.; Pouponnot, C.; Stella, L.; Gbocchinfuso, G. Bocchinfuso; Nkatsanis, N. Katsanis; KSol-Church, K. Sol-Church. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 96:5(2015), pp. 816-825. [10.1016/j.ajhg.2015.03.001]
File allegati a questo prodotto
File Dimensione Formato  
Niceta_Mutations_2015.pdf

accesso aperto

Note: Adobe PDF
Tipologia: Documento in Post-print (versione successiva alla peer review e accettata per la pubblicazione)
Licenza: Creative commons
Dimensione 1.57 MB
Formato Adobe PDF
1.57 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/783132
Citazioni
  • ???jsp.display-item.citation.pmc??? 37
  • Scopus 91
  • ???jsp.display-item.citation.isi??? 86
social impact