Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene

Andrés Hidalgo, Songhui Ma, Anna J. Peired, Linnea A. Weiss, Charlotte Cunningham-Rundles, Paul S. Frenette

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1705-1712
Number of pages8
JournalBlood
Volume101
Issue number5
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

Fingerprint

Guanosine Diphosphate Fucose
Fucose
Adhesion
Genes
Selectins
Mutation
Neutrophils
Ligands
Severe Combined Immunodeficiency
Venules
Golgi Apparatus
Missense Mutation
Mutant Proteins
Fibroblasts
Hemolysis
Neutropenia
Intellectual Disability
Open Reading Frames
Endothelium
Oral Administration

ASJC Scopus subject areas

  • Hematology

Cite this

Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. / Hidalgo, Andrés; Ma, Songhui; Peired, Anna J.; Weiss, Linnea A.; Cunningham-Rundles, Charlotte; Frenette, Paul S.

In: Blood, Vol. 101, No. 5, 01.03.2003, p. 1705-1712.

Research output: Contribution to journalArticle

Hidalgo, Andrés ; Ma, Songhui ; Peired, Anna J. ; Weiss, Linnea A. ; Cunningham-Rundles, Charlotte ; Frenette, Paul S. / Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. In: Blood. 2003 ; Vol. 101, No. 5. pp. 1705-1712.
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