title: A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14.
abstract: Lysosome-related organelles have versatile functions, including protein and lipid degradation, signal transduction and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal-lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system. Here, we describe a previously unknown human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated protein kinase (MAPK) signaling to late endosomes, is crucial for the function of neutrophils, B cells, cytotoxic T cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3' untranslated region (UTR) of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a previously unknown role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity.
authors.affiliation: Department of Pediatric Hematology/Oncology Carl Hannover Medical School, Carl Neuberg Strasse 1 D-30625 Hannover, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Bohn
authors.forename: Anna
authors.initials: A
authors.lastname: Allroth
authors.forename: Gudrun
authors.initials: G
authors.lastname: Brandes
authors.forename: Jens
authors.initials: J
authors.lastname: Thiel
authors.forename: Erik
authors.initials: E
authors.lastname: Glocker
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Chozhavendan
authors.initials: C
authors.lastname: Rathinam
authors.forename: Nicole
authors.initials: N
authors.lastname: Taub
authors.forename: David
authors.initials: D
authors.lastname: Teis
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Dewey
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001483:Base Sequence; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005192:Family Health; D005260:Female; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007958:Leukocyte Count; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000648:ultrastructure; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis
chemical_list: D033964:Adaptor Protein Complex 4; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D011993:Recombinant Fusion Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D008156:Luciferases