Collaborative Study: Vitamin B12 Therapy for Spliceosomopathy

Researchers from the Max Planck Institute for Biology of Ageing and the Department of Pediatrics and Adolescent Medicine at University Hospital Cologne investigated this splicing factor in humans and the nematode Caenorhabditis elegans.

In the animal model, defects in the splicing factor resulted in developmental and growth abnormalities similar to those observed in humans. Metabolic and lipid analyses revealed that PUF60 dysfunction particularly affects one-carbon metabolism, leading to methionine depletion and alterations in phospholipid remodeling. These changes activated the integrated stress response and reduced the activity of the mTORC1 signaling pathway, which regulates cell growth. Treatment with vitamin B12 was able to correct these developmental deficits in C. elegans.

"We were surprised to discover that defects in the fundamental process of RNA processing have such a specific impact on vitamin B12-dependent metabolism," says Jonathan Kölschbach, first author of the study. Cellular analyses and blood samples from affected patients also provided evidence of comparable metabolic changes in individuals with this rare disorder. The series of publications appeared in the scientific journals Nature Communications, GeneReviews, International Journal of Molecular Sciences (IJMS), and Nature Aging.

To investigate whether the metabolic changes observed in the model organism might also play a role in humans, the team at the Max Planck Institute for Biology of Ageing (MPIAGE) worked closely with the Department of Pediatrics and Adolescent Medicine and the Center for Rare Diseases (CESEK) at University Hospital Cologne.

"Our study is a good example of how basic systems biology research using model organisms can provide new insights into human diseases," says Prof. Dr. Adam Antebi, Director at the Max Planck Institute for Biology of Ageing.

"Monogenic disorders are unique paradigmatic models for understanding fundamental metabolic mechanisms. Our work consistently aims to translate insights from cell biology directly into targeted strategies that are appropriate for affected children and adolescents," says PD Dr. Hormos Clas Dafsari, Senior Physician in Pediatric Neurology, Head of the Cellular Resilience Mechanisms & Molecular Modulation Research Group at the Department of Pediatrics and Adolescent Medicine and at the Center for Molecular Medicine Cologne (CMMC).

The findings open up a new avenue of research into other disorders involving impaired RNA splicing, with the aim of determining whether vitamin B12 could also influence metabolic alterations or disease symptoms in affected patients. To address this question, further preclinical studies in neuronal cells are being conducted with approximately €300,000 in funding awarded to Dr. Dafsari through a German Research Foundation (DFG) research grant (DFG project no. 578221361).

As part of this research, his group is investigating additional cellular effects of vitamin B12 on the mTOR and autophagy pathways. Preparations are currently underway for potential controlled clinical trials, drawing on resources available at the Department of Pediatrics and Adolescent Medicine, including its specialized ORPHANET-registered outpatient clinic within the Center for Rare Syndromic Diseases, as well as international patient registries.

Original Publications:

Kölschbach J, Dafsari HS, Baum E, Löhrke A, Kew C, Dikic I, Huang W, Antebi A. “Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.”, Nat Commun. 2026 Aug 7;17(1):8011. doi: 10.1038/s41467-026-76295-9. 

Baum E, Kölschbach J, Huang W, Antebi A, Dafsari HS. “PUF60-Related Disorders.” 2026 Jul 28. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 42520151.

Baum E, Huang W, Vincent-Delorme C, Brunelle P, Antebi A, Dafsari HS. “Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders.”, Int J Mol Sci. 2024 Feb 8;25(4):2053. doi: 10.3390/ijms25042053. 

Huang W, Kew C, Fernandes SA, Löhrke A, Han L, Demetriades C, Antebi A. “Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.” Nat Aging. 2022 Sep;2(9):796-808. doi: 10.1038/s43587-022-00275-z.

This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications team of the University Hospital Cologne (original German version here).