Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene.
Leukocyte adhesion deficiency type 2 (LADII) is characterized by defective selectin ligand formation, recurrent infection, and mental retardation. This rare syndrome has only been described in 2 kindreds of Middle Eastern descent who have differentially responded to exogenous fucose treatment. The molecular defect was recently ascribed to single and distinct missense mutations in a putative Golgi guanosine diphosphate (GDP)-fucose transporter. Here, we describe a patient of Brazilian origin with features of LADII. Sequencing of the GDP-fucose transporter revealed a novel single nucleotide deletion producing a shift in the open-reading frame and severe truncation of the polypeptide. Overexpression of the mutant protein in the patient's fibroblasts did not rescue fucosylation, suggesting that the deletion ablated the activity of the transporter. Administration of oral L-fucose to the patient produced molecular and clinical responses, as measured by the appearance of selectin ligands, normalization of neutrophil counts, and prevention of infectious recurrence. The lower neutrophil counts paralleled improved neutrophil interactions with activated endothelium in cremasteric venules of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, fucose supplementation induced autoimmune neutropenia and the appearance of H antigen on erythrocytes, albeit without evidence of intravascular hemolysis. The robust response to fucose despite a severely truncated transporter suggests alternative means to transport GDP-fucose into the Golgi complex.
Hidalgo
Andrés
A
Divisions of Hematology and Clinical Immunology, Department of Medicine, Mount Sinai School of Medicine, New York, NY.
Ma
Songhui
S
Peired
Anna J
AJ
Weiss
Linnea A
LA
Cunningham-Rundles
Charlotte
C
Frenette
Paul S
PS
D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000139:chemically induced; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D002658:Developmental Disabilities / Q000235:genetics; D019040:E-Selectin / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005643:Fucose / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000235:genetics; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009004:Monosaccharide Transport Proteins; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000276:immunology; D019007:P-Selectin / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
D001323:Autoantibodies; D002352:Carrier Proteins; D019040:E-Selectin; D009004:Monosaccharide Transport Proteins; D019007:P-Selectin; C426650:SLC35C1 protein, human; D005643:Fucose