A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14.
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.
Bohn
Georg
G
Department of Pediatric Hematology/Oncology Carl Hannover Medical School, Carl Neuberg Strasse 1 D-30625 Hannover, Germany.
Allroth
Anna
A
Brandes
Gudrun
G
Thiel
Jens
J
Glocker
Erik
E
Schäffer
Alejandro A
AA
Rathinam
Chozhavendan
C
Taub
Nicole
N
Teis
David
D
Zeidler
Cornelia
C
Dewey
Ricardo A
RA
Geffers
Robert
R
Buer
Jan
J
Huber
Lukas A
LA
Welte
Karl
K
Grimbacher
Bodo
B
Klein
Christoph
C
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
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