CLPB Mutations Cause 3-Methylglutaconic Aciduria, Progressive Brain Atrophy, Intellectual Disability, Congenital Neutropenia, Cataracts, Movement Disorder

Abstract

We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

“…The excretion of 3‐MGC can be highly variable or intermittently normal in secondary 3‐MGA and is generally less than levels seen in primary 3‐MGA due to AUH . Clinical features of secondary 3‐MGA are heterogeneous but distinctive, rare, but highly characteristic, neurometabolic syndromes (Saunders et al, 2015; Wortmann et al, 2013, 2015). …”

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

“…We and others have demonstrated previously the utility of zebrafish models in testing the candidacy of rare mutations in syndromic disorders; [14][15][16][17][18][19][20][21] this approach includes an experimental paradigm in which expression of mutations in the context of spliced isoforms can be used for testing the specific effect of such alleles. 14,22-24 For TMEM260, we utilized this approach to ask (1) whether the transient suppression or introduction of deletions at the locus can reproduce key aspects of the human pathology, (2) whether the two known isoforms of the human locus might have different abilities to rescue relevant phenotypes, and (3) whether the long TMEM260 isoform harboring individual 2-II-4's mutation (c.1698_1701del) has the ability to rescue relevant phenotypes.…”

A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients

“…Recently autosomal recessive mutations in CLPB have been shown to cause a genetic syndrome with a broad phenotypic spectrum (MIM #616254) (Wortmann et al 2015;Saunders et al 2015;Kanabus et al 2015;Capo-Chichi et al 2015). The neurological presentation ranges from normal development without intellectual deficits to a severe and progressive encephalopathy associated with muscular hypertonia, progressive brain atrophy and movement disorder.…”

“…The exact function of human ClpB remains elusive, although the bacterial homologue acts as a chaperone involved in disaggregation of misfolded proteins (Rosenzweig et al 2013) 5 . In two independent zebrafish models of CLPB defects, neurological features (cerebellar hypoplasia, abnormal touch-evoked response with increased swim velocity and tail beat frequency) reflect the human phenotype (Wortmann et al 2015;Capo-Chichi et al 2015).…”

“…CLPB encodes caseinolytic peptidase B homologue ClpB, a member of the AAA+ protein family with mitochondrial localization (Wortmann et al 2015). The exact function of human ClpB remains elusive, although the bacterial homologue acts as a chaperone involved in disaggregation of misfolded proteins (Rosenzweig et al 2013) 5 .…”