title: Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.
abstract: Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42(∗)), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs(∗)20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex.
authors.affiliation: Institute of Human Genetics, University of Erlangen, D-91054 Erlangen, Germany. Electronic address: rami.aboujamra@uk-erlangen.de.
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
authors.affiliation: INSERM U781, Fondation IMAGINE, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Orianne
authors.initials: O
authors.lastname: Philippe
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel.
authors.forename: Annick
authors.initials: A
authors.lastname: Raas-Rothschild
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Eck
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, University of Erlangen, D-91054 Erlangen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: INSERM U781, Fondation IMAGINE, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: Institute of Human Genetics, University of Erlangen, D-91054 Erlangen, Germany.
authors.forename: Arif
authors.initials: A
authors.lastname: Ekici
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, D-53127 Bonn, Germany; Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Felix F
authors.initials: FF
authors.lastname: Brockschmidt
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, D-53127 Bonn, Germany; Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: INSERM U781, Fondation IMAGINE, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, D-80634 München, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, University of Erlangen, D-91054 Erlangen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Reis
authors.affiliation: INSERM U781, Fondation IMAGINE, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France. Electronic address: laurence.colleaux@inserm.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000235:genetics*; D000293:Adolescent; D002605:Character; D002648:Child; D005260:Female; D008040:Genetic Linkage; D040821:Human Characteristics; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010264:Paraplegia / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: C000604469:AP4S1 protein, human; D033964:Adaptor Protein Complex 4