TY - JOUR
T1 - Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature
AU - Abou Jamra, Rami
AU - Philippe, Orianne
AU - Raas-Rothschild, Annick
AU - Eck, Sebastian H.
AU - Graf, Elisabeth
AU - Buchert, Rebecca
AU - Borck, Guntram
AU - Ekici, Arif
AU - Brockschmidt, Felix F.
AU - Nöthen, Markus M.
AU - Munnich, Arnold
AU - Strom, Tim M.
AU - Reis, Andre
AU - Colleaux, Laurence
N1 - Funding Information:
We are grateful to the families for their participation in the study. We also thank Angelika Diem, Petra Rothe, Bianca Schmick, and Anna Benet-Pagès for the excellent technical support. This study was supported by the Centre National de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (ANR-08-MNP-010), the Ministère de la Recherche et de l'Enseignement Supérieur, the German Intellectual disability Network (MRNET) through a grant from the German Ministry of Research and Education to A. Reis and T. Strom (01GS08160 and 01GR0804-4), the European Commission 7th Framework Program, Project N. 261123, GEUVADIS, and by the Deutsche Forschungsgemeinschaft (DFG) (AB393/1-2).
PY - 2011/6/10
Y1 - 2011/6/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79958820932&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.04.019
DO - 10.1016/j.ajhg.2011.04.019
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C2 - 21620353
AN - SCOPUS:79958820932
SN - 0002-9297
VL - 88
SP - 788
EP - 795
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -