期刊
BLOOD
卷 139, 期 5, 页码 779-791出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021010762
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资金
- National Institutes of Health (NIH)
- Eunice Kennedy Shriver National Institute of Child Health and Human Devel-opment Institutional National Research Service Award Training Pro-gram in Developmental Hematology [T32 HD007499-19]
- Training of the Pediatric Physician-Scientist [T32 HD043010]
- American Soci-ety of Hematology Scholar Award
- Children's Discovery Institute Fellowship [MC-F-2020-871]
- NIH, National Institute on Aging [F31 AG060672]
- NIH, National Institute of General Medical Sciences grant [T32 GM008275]
- Blavatnik Family Foundation Fel-lowship
- NIH, National Cancer Institute grant [K08 CA190815]
- G. Harold and Leila Y. Mathers Foundation
- NIH, National Institute of General Medical Sciences [R01 GM099836]
- INSERM ITMO Sante publique
- X4 Pharma
- Prolong Pharma
- Chugai SA (French SCN Registry)
- Foundation for Rare Diseases [AO9102LS]
- 111 Les Arts, Association pour la Recherche et les Maladies Hematologiques de l'Enfant, Association de Barth
- Association Sportive de Saint Quentin Fallavier
- NIH, National Institute of Allergy and Infectious Dis-eases grant [2R 24 AI 049393]
- US Department of Defense grant [BM130173]
- NIH, National Heart, Lung, and Blood Institute [R01 HL152632-01]
Genetic analysis of patients with congenital neutropenia revealed an association between CLPB variants and the disease. CLPB variants obstruct the differentiation of granulocytes and increase apoptosis, contributing to the development of neutropenia. This study provides new insights into the diagnosis and treatment of congenital neutropenia.
Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondria! function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.
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