title: Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies.
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.
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy; Polo di Ricerca - Malattie rare, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, 00146 Italy.
authors: Marcello
authors: M
authors: Niceta
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy.
authors: Emilia
authors: E
authors: Stellacci
authors: Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA.
authors: Karen W
authors: KW
authors: Gripp
authors: Istituto di Pediatria, Università Cattolica del Sacro Cuore, Rome, 00168 Italy.
authors: Giuseppe
authors: G
authors: Zampino
authors: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors: Maria
authors: M
authors: Kousi
authors: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata," Rome, 00133 Italy.
authors: Massimiliano
authors: M
authors: Anselmi
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy; Dipartimento di Medicina Sperimentale, Università "La Sapienza," 00161 Rome, Italy.
authors: Alice
authors: A
authors: Traversa
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy.
authors: Andrea
authors: A
authors: Ciolfi
authors: Center for Pediatric Research, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA.
authors: Deborah
authors: D
authors: Stabley
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy.
authors: Alessandro
authors: A
authors: Bruselles
authors: Dipartimento di Medicina Sperimentale, Università "La Sapienza," 00161 Rome, Italy.
authors: Viviana
authors: V
authors: Caputo
authors: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, 00161 Italy.
authors: Serena
authors: S
authors: Cecchetti
authors: Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, Rome, 00198 Italy.
authors: Sabrina
authors: S
authors: Prudente
authors: Dipartimento di Psicologia, Sezione di Neuroscienze, Università "La Sapienza," Rome, 00161 Italy.
authors: Maria T
authors: MT
authors: Fiorenza
authors: Sezione di Istologia e Embriologia Medica, Dipartimento di Scienze Anatomiche, Istologiche, Medico-legali e dell'Apparato Locomotore, Università "La Sapienza," Rome, 00161 Italy.
authors: Carla
authors: C
authors: Boitani
authors: Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, 13385 France.
authors: Nicole
authors: N
authors: Philip
authors: Division of Medical Genetics, Ochsner Health System, New Orleans, LA 70121, USA.
authors: Dmitriy
authors: D
authors: Niyazov
authors: Istituto di Pediatria, Università Cattolica del Sacro Cuore, Rome, 00168 Italy.
authors: Chiara
authors: C
authors: Leoni
authors: Department of Pediatrics, Center for Genetic Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898 Japan.
authors: Takaya
authors: T
authors: Nakane
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA.
authors: Kim
authors: K
authors: Keppler-Noreuil
authors: Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Stephen R
authors: SR
authors: Braddock
authors: Institut für Humangenetik, Universität zu Lübeck, Lübeck, 23538 Germany.
authors: Gabriele
authors: G
authors: Gillessen-Kaesbach
authors: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata," Rome, 00133 Italy.
authors: Antonio
authors: A
authors: Palleschi
authors: Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, H3T 1C5 Canada.
authors: Philippe M
authors: PM
authors: Campeau
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Brendan H L
authors: BH
authors: Lee
authors: Institut Curie Centre de Recherche, CNRS UMR 3347, INSERM U1021, Paris Sud University, Orsay, 91405 France.
authors: Celio
authors: C
authors: Pouponnot
authors: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata," Rome, 00133 Italy.
authors: Lorenzo
authors: L
authors: Stella
authors: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata," Rome, 00133 Italy.
authors: Gianfranco
authors: G
authors: Bocchinfuso
authors: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors: Nicholas
authors: N
authors: Katsanis
authors: Center for Pediatric Research, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA.
authors: Katia
authors: K
authors: Sol-Church
authors: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy; Polo di Ricerca - Malattie rare, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, 00146 Italy. Electronic address: marco.tartaglia@iss.it.
authors: Marco
authors: M
authors: Tartaglia
mesh_terms: D002386:Cataract / Q000235:genetics* / Q000473:pathology; D003638:Deafness / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics*; D012640:Seizures / Q000235:genetics / Q000473:pathology
chemical_list: C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D038362:Glycogen Synthase Kinase 3