WHIM syndrome

Disease ID:953
Name:WHIM syndrome
Associated with:1 target
1 immuno-relevant target
1 immuno-relevant ligand
Synonyms
Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) | Warts-Infections-Leukopenia-Myelokatexis (WILM)
Description
WHIM syndrome is an extremely rare congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow (myelokathexis) and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to human papillomavirus (HPV) induced lesions (cutaneous warts, genital dysplasia and invasive mucosal carcinoma) (from orphanet).
Database Links
OMIM: 193670
Orphanet: ORPHA51636

Targets

CXCR4
Comments:  Truncating mutations in the cytoplasmic tail domain of the CXCR4 gene have been identified in almost all cases of WHIM syndrome. The mutations result in receptor gain of function (i.e. prolonged agonist-dependent signalling). Mutations in CXCR4 that augment its activity have been identified in patients with WHIM syndrome. Such mutations can impair CXCR4/β-arrestin interaction and β-arrestin-mediated signal attenuation. This effect leads to defective desensitization and internalization of CXCR4 in response to ligand (CXCL12; SDF1) activation; in effect, increased CXCR4 activity.
References:  2-3
Ligand interactions: 
Ligand Comments
X4P-001
Phase 2/3 clinical candidate for Whim disease.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
X4P-001
Immuno Disease Comments: Phase 2/3 clinical candidate for Whim disease.
Clinical Use: NCT03005327 trial of X4P-001 in Patients With WHIM Syndrome. | View clinical data
Bioactivity Comments: AMD070 potently inhibits T-tropic (X4) HIV-1 replication in vitro [5]. | View biological activity

References

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1. Balabanian K, Lagane B, Pablos JL, Laurent L, Planchenault T, Verola O, Lebbe C, Kerob D, Dupuy A, Hermine O et al.. (2005) WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood, 105 (6): 2449-57. [PMID:15536153]

2. Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA. (2003) Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet, 34: 70-74. [PMID:12692554]

3. Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P et al.. (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood, 123 (11): 1637-46. [PMID:24366360]

4. Lagane B, Chow KY, Balabanian K, Levoye A, Harriague J, Planchenault T, Baleux F, Gunera-Saad N, Arenzana-Seisdedos F, Bachelerie F. (2008) CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood, 112 (1): 34-44. [PMID:18436740]

5. Skerlj RT, Bridger GJ, Kaller A, McEachern EJ, Crawford JB, Zhou Y, Atsma B, Langille J, Nan S, Veale D et al.. (2010) Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J. Med. Chem., 53 (8): 3376-88. [PMID:20297846]