ID

45957

Descrizione

Principal Investigator: Philip M. Murphy, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA MeSH: WHIM syndrome,Warts,Severe congenital neutropenia,Hypogammaglobulinemia,Warts, hypogammaglobulinemia, infections, and myelokathexis https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000856 We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor *CXCR4*. We have identified a patient born with WHIM syndrome and the WHIM mutation *CXCR4supR334X/sup* who has been disease-free for 20 years and who lacks *CXCR4supR334X/sup* in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele *CXCR4supR334X/sup* and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective *Cxcr4* haploinsufficiency (inactivation of one copy of *Cxcr4* and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that *CXCR4* knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

collegamento

dbGaP study=phs000856

Keywords

versioni (1)

1. 16/03/24 16/03/24 - Madita Rudolph

Titolare del copyright

Philip M. Murphy, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

Caricato su

16 marzo 2024

DOI

Per favore, per richiedere un accesso.

Licenza