Hereditary biallelic mutations in the CLPB gene are the cause of congenital neutropenia
associated with MEGCANN, a rare autosomal recessive disease (OMIM entry #616271). In its
severe form, the disease leads to death by a few months of age as a result of significant neurologic
symptoms or life-threatening infections. Recently identified de novo monoallelic mutations in the
CLPB gene act in a dominant-negative manner and also cause severe congenital neutropenia.
The CLPB gene encodes a broadly expressed mitochondrial protein containing several ankyrin
repeats and a single AAA+ (ATPases Associated with diverse cellular Activities) module. The
molecular mechanism of CLPB function in neutrophil precursor cells is not known, and the
mitochondrial defects elicited by mutated CLPB variants and their link to defective granulopoiesis
are poorly defined. We hypothesize that CLPB is essential for the metabolic shift from glycolysis
to mitochondrial respiration during neutrophil differentiation. We will test this hypothesis by
completing two Specific Aims. In Aim 1, we will determine the role of CLPB in mitochondrial
morphology, metabolism, and neutrophil differentiation using myeloblastic cell line models of
granulopoiesis. This Aim will test the sub-hypothesis that CLPB plays an essential role in
mitochondrial remodeling and metabolic reprogramming during neutrophil differentiation. In Aim
2, we will examine the effect of disease mutations on the interactions between CLPB and key
regulators of mitochondrial dynamics and cristae morphology. This Aim will test the sub-
hypothesis that the principal difference between the effects of biallelic vs. monoallelic mutations
on the CLPB activity arises from distinct interaction propensities of the mutated CLPB variants.
At the outcome, our studies will provide a new insight into the role of CLPB in neutrophil
differentiation, will help understand the molecular defects of the disease CLPB variants, and will
set the stage for developing potential treatments for neutropenias caused by CLPB mutations.