title: WHIM Syndrome Caused by Waldenström's Macroglobulinemia-Associated Mutation CXCR4 (L329fs).
abstract: WHIM syndrome is an autosomal dominant immunodeficiency disease caused by mutations affecting the carboxy-terminus of CXCR4. To characterize novel genetic causes of the syndrome, we recruited a pediatric patient with possible WHIM syndrome, performed CXCR4 gene sequencing and compared his clinical phenotype and CXCR4 tail amino acid sequences with other patients with WHIM syndrome carrying CXCR4 (R334X) mutations. We identified and biochemically characterized a heterozygous 5 base pair deletion (nucleotides 986-990) located in the portion of the open reading frame (ORF) of CXCR4 that encodes the carboxy-terminal domain of the receptor. This CXCR4 (L329fs) mutation causes a frame-shift at codon 329 resulting in replacement of the final 24 predicted amino acids of the receptor with 12 missense amino acids. Like previously reported WHIM mutations, this frame-shift mutation CXCR4 (L329fs) decreased receptor downregulation in response to the CXCR4 agonist CXCL12 in patient PBMCs as well as in transfected K562 and HEK 293 cells, but increased calcium flux responses in K562 cells to CXCL12 stimulation. Thus, CXCR4 (L329fs) appears to be a de novo autosomal dominant frame-shift gain-of-function mutation that like other carboxy-terminus mutations causes WHIM syndrome. The same CXCR4 (L329fs) frame-shift variant has been reported to occur in tumor cells from a patient with Waldenström's Macroglobulemia (WM), but is caused by a distinct genetic mechanism: insertion of a single nucleotide in the L329 codon, providing additional evidence that the carboxy-terminus of CXCR4 is a genetic hotspot for mutation.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Catherina
authors.initials: C
authors.lastname: Pan
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Lizbeeth
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Velez
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Anaya-O'Brien
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Ulrick
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Littel
authors.affiliation: Pediatric Hematology/Oncology, East Tennessee Children's Hospital, Knoxville, TN, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Corns
authors.affiliation: Allergy and Asthma Affiliates, Knoxville, TN, USA.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Ellenburg
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11 N107, Bethesda, MD, 20892-1886, USA. dmcdermott@niaid.nih.gov.
authors.forename: David H
authors.initials: DH
authors.lastname: McDermott
mesh_terms: D002675:Child, Preschool; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D020014:K562 Cells; D008297:Male; D009154:Mutation; D009503:Neutropenia / Q000235:genetics; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics*; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics*; D014860:Warts / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4
keywords: CXCR4; WHIM syndrome; gain of function; immunodeficiency; internalization; mutation