The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.

] University Medical Center Hamburg Eppendorf Bioinformatics Service Facility Hamburg Germany [2] Center for Bioinformatics University of Hamburg Hamburg Germany [3] Heinrich Pette Institute Leibniz Institute for Experimental Virology Virus Genomics Hamburg Germany

Center for Bioinformatics University of Hamburg Hamburg Germany

Department of Clinical Genetics Institute of Biology and Medical Genetics University Hospital Motol 2nd Medical School Charles University Prague Prague Czech Republic

Department of Pediatric Neurology Charles University 2nd Faculty of Medicine Motol Hospital Prague Czech Republic

Institute of Human Genetics University Medical Center Hamburg Eppendorf Hamburg Germany

Zobrazit více v PubMed

Abou Jamra R, Philippe O, Raas-Rothschild A, et al. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011;88:788–795. PubMed PMC

Hirst J, Irving C, Borner GH. Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia. Traffic. 2013;14:153–164. PubMed

McNiven MA, Thompson HM. Vesicle formation at the plasma membrane and trans-Golgi network: the same but different. Science. 2006;313:1591–1594. PubMed

Dell'Angelica EC, Mullins C, Bonifacino JS. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem. 1999;274:7278–7285. PubMed

Hirst J, Bright NA, Rous B, Robinson MS. Characterization of a fourth adaptor-related protein complex. Mol Biol Cell. 1999;10:2787–2802. PubMed PMC

Verkerk AJ, Schot R, Dumee B, et al. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009;85:40–52. PubMed PMC

Moreno-De-Luca A, Helmers SL, Mao H, et al. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J Med Genet. 2011;48:141–144. PubMed PMC

Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63. PubMed

Blumkin L, Lerman-Sagie T, Lev D, Yosovich K, Leshinsky-Silver E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J Neurol Sci. 2011;305:67–70. PubMed

Bauer P, Leshinsky-Silver E, Blumkin L, et al. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) Neurogenetics. 2012;13:73–76. PubMed

Kong XF, Bousfiha A, Rouissi A, et al. A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. PLoS One. 2013;8:e58286. PubMed PMC

Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307–328. PubMed PMC

Borck G, Molla-Herman A, Boddaert N, et al. Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome. Hum Mutat. 2008;29:966–974. PubMed

Cacciagli P, Desvignes JP, Girard N, et al. AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome) Eur J Hum Genet. 2013;22:363–368. PubMed PMC

Montpetit A, Cote S, Brustein E, et al. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 2008;4:e1000296. PubMed PMC

Saillour Y, Zanni G, Des Portes V, et al. Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia. J Med Genet. 2007;44:739–744. PubMed PMC

Tarpey PS, Stevens C, Teague J, et al. Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation. Am J Hum Genet. 2006;79:1119–1124. PubMed PMC

Dell'Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky–Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell. 1999;3:11–21. PubMed

Nesbit MA, Hannan FM, Howles SA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013;45:93–97. PubMed PMC

Matsuda S, Miura E, Matsuda K, et al. Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4. Neuron. 2008;57:730–745. PubMed