WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
Blood
; 105(6): 2449-57, 2005 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-15536153
ABSTRACT
The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/CXCR4 axis. We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Códon sem Sentido
/
Receptores CXCR4
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Quimiocinas CXC
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Característica Quantitativa Herdável
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Doenças Genéticas Inatas
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Síndromes de Imunodeficiência
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
França