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Vitamin B12 alleviates Verheij syndrome-like defects via phospholipid remodeling in a C. elegans PUF60 spliceosomopathy model

ABSTRACT: Verheij syndrome (VRJS) is a rare genetic disorder caused by mutations in the poly(U)-binding splicing factor 60 (PUF60), a core component of the spliceosomal complex. VRJS triggers multiple congenital anomalies, but the underlying pathomechanisms remain poorly understood. Mutation of the Caenorhabditis elegans PUF60 ortholog, rnp-6, recapitulates several hallmarks of VRJS, including growth delay and smaller body size. Here, we demonstrate that developmental defects in rnp-6 mutants are rescued by dietary K12-type E. coli strains. Through complementary genetic screens and multiomic analysis, we identify vitamin B12 as a potent suppressor of these defects, acting via the methionine/S-adenosylmethionine/phosphatidylcholine metabolic axis. Mechanistically, rnp-6 mutation causes aberrant splicing of metabolism-related genes and nhr-114, an HNF4 homolog and transcriptional master regulator of lipid and one-carbon metabolism, leading to impaired cellular methylation potential, dysregulated phospholipid metabolism, and activation of the integrated stress response (ISR). Vitamin B12 supplementation restores metabolic balance, suppresses ISR, and activates mTORC1 signaling to rescue growth and developmental phenotypes. Remarkably, restoration of nhr-114 splicing alone suffices to correct rnp-6 developmental defects. Our findings establish C. elegans as a tractable model of PUF60-deficiency, and suggest VB12 as a promising therapeutic strategy to mitigate VRJS-related anomalies.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE307065 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Animals can thrive on variable food resources as a result of autonomous processes and beneficial relationships with their gut microbes. Food intake elicits major physiological changes, which are compensated with transient systemic responses that maintain homeostasis in the organism. This integration of external information occurs through cellular sensory elements, such as nuclear receptors, which modulate gene expression in response to specific cues. Given the importance of the germline stem cells (GSCs) for the development of the germ line and the continuity of the species, it is reasonable to assume that GSCs might be shielded from the negative influence of environmental perturbations. To our knowledge, however, there are no mechanisms reported that protect proliferating germ cells from harmful dietary metabolites. Using Caenorhabditis elegans as a model, we report that the somatic activity of the conserved nuclear receptor nhr-114/HNF4 protects GSC divisions and GSC integrity from dietary metabolites. In the absence of nhr-114 and on certain bacterial diets, otherwise somatically normal animals accumulate germ cell division defects during development and become sterile. We find that in nhr-114(-) animals the induction of germline defects and sterility depends on the bacterial metabolic status with respect to the essential amino acid tryptophan. This illustrates an animal-microbe interaction in which somatic nuclear receptor activity preserves the germline by buffering against dietary metabolites, likely through a somatic detoxifying response. Overall, our findings uncover an unprecedented and presumably evolutionary conserved soma-to-germline axis of communication that maintains reproductive robustness on variable food resources. Trasncriptional profiles of adult sterile nhr-114(RNAi) animals were compared to those of sterile glp-1(q224ts) animals. Independently, the transcriptional profiles of wild type animals fed an OP50 diet supplemented with Tryptophan was compared to wild type animals fed a standard OP50 diet.

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Vitamin B12 alleviates Verheij syndrome-like defects via phospholipid remodeling in a C. elegans PUF60 spliceosomopathy model

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