Heterozygous variants of CLPB are a cause of severe congenital neutropenia.

Autor:	Warren JT; Division of Hematology-Oncology, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO., Cupo RR; Department of Biochemistry and Biophysics, Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Wattanasirakul P; Division of Oncology, Department of Medicine, Washington University School of Medicine, St, MO., Spencer DH; Division of Oncology, Department of Medicine, Washington University School of Medicine, St, MO., Locke AE; Division of Oncology, Department of Medicine, Washington University School of Medicine, St, MO., Makaryan V; Department of Medicine, University of Washington, Seattle, WA., Bolyard AA; Department of Medicine, University of Washington, Seattle, WA., Kelley ML; Department of Medicine, University of Washington, Seattle, WA., Kingston NL; Medical Scientist Training Program, Washington University School of Medicine, St, MO., Shorter J; Department of Biochemistry and Biophysics, Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Bellanné-Chantelot C; Département de Génétique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié Salpêtrière, Sorbonne Université, Paris, France; and., Donadieu J; Sorbonne Université, INSERM, AP-HP, Registre français des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Hôpital Trousseau, Service Hémato Oncologie Pédiatrique, Paris, France., Dale DC; Department of Medicine, University of Washington, Seattle, WA., Link DC; Division of Oncology, Department of Medicine, Washington University School of Medicine, St, MO.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Feb 03; Vol. 139 (5), pp. 779-791.
DOI:	10.1182/blood.2021010762
Abstrakt:	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 mitochondrial 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. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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