An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.
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.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hengameh
H
Abdollahpour
1] 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.
Malik
M
Alawi
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fanny
F
Kortüm
Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
Michael
M
Beckstette
Department of Clinical Genetics, Institute of Biology and Medical Genetics, University Hospital Motol, Second Medical School, Charles University Prague, Prague, Czech Republic.
Eva
E
Seemanova
Department of Pediatric Neurology, Charles University, Second Faculty of Medicine, Motol Hospital, Prague, Czech Republic.
Vladimír
V
Komárek
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Georg
G
Rosenberger
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Kerstin
K
Kutsche
D033964:Adaptor Protein Complex 4 / Q000235:genetics*; D000293:Adolescent; D002648:Child; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D011782:Quadriplegia / Q000175:diagnosis / Q000235:genetics*; D035781:Siblings; D013577:Syndrome
D033964:Adaptor Protein Complex 4