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Am J Hum Genet. 2015 May 7;96(5):816-25. doi: 10.1016/j.ajhg.2015.03.001. Epub 2015 Apr 9.

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies.

Author information

1
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.
2
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy.
3
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA.
4
Istituto di Pediatria, Università Cattolica del Sacro Cuore, Rome, 00168 Italy.
5
Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
6
Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma "Tor Vergata," Rome, 00133 Italy.
7
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, 00161 Italy; Dipartimento di Medicina Sperimentale, Università "La Sapienza," 00161 Rome, Italy.
8
Center for Pediatric Research, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA.
9
Dipartimento di Medicina Sperimentale, Università "La Sapienza," 00161 Rome, Italy.
10
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, 00161 Italy.
11
Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, Rome, 00198 Italy.
12
Dipartimento di Psicologia, Sezione di Neuroscienze, Università "La Sapienza," Rome, 00161 Italy.
13
Sezione di Istologia e Embriologia Medica, Dipartimento di Scienze Anatomiche, Istologiche, Medico-legali e dell'Apparato Locomotore, Università "La Sapienza," Rome, 00161 Italy.
14
Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, 13385 France.
15
Division of Medical Genetics, Ochsner Health System, New Orleans, LA 70121, USA.
16
Department of Pediatrics, Center for Genetic Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898 Japan.
17
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA.
18
Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
19
Institut für Humangenetik, Universität zu Lübeck, Lübeck, 23538 Germany.
20
Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, H3T 1C5 Canada.
21
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
22
Institut Curie Centre de Recherche, CNRS UMR 3347, INSERM U1021, Paris Sud University, Orsay, 91405 France.
23
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.

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.

PMID:
25865493
PMCID:
PMC4570552
DOI:
10.1016/j.ajhg.2015.03.001
[Indexed for MEDLINE]
Free PMC Article

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