Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature

Rami Abou Jamra, Orianne Philippe, Annick Raas-Rothschild, Sebastian H. Eck, Elisabeth Graf, Rebecca Buchert, Guntram Borck, Arif Ekici, Felix F. Brockschmidt, Markus M. Nöthen, Arnold Munnich, Tim M. Strom, Andre Reis, Laurence Colleaux*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

196 Scopus citations

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.

Original languageEnglish
Pages (from-to)788-795
Number of pages8
JournalAmerican Journal of Human Genetics
Volume88
Issue number6
DOIs
StatePublished - 10 Jun 2011
Externally publishedYes

Funding

FundersFunder number
European Commission 7th Framework Program
German Ministry of Research and Education01GR0804-4, 01GS08160
Seventh Framework Programme261123
Deutsche ForschungsgemeinschaftAB393/1-2
Agence Nationale de la RechercheANR-08-MNP-010
Ministère de l'Enseignement Supérieur et de la Recherche
Centre National de la Recherche Scientifique

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