Investigation on a MMACHC mutant from cblC disease The c.394C>T variant

Rosa Passantino, Maria Rosalia Mangione, Maria Grazia Ortore, Maria Assunta Costa, Alessia Provenzano, Heinz Amenitsch, Raffaele Sabbatella, Caterina Alfano, Vincenzo Martorana*, Silvia Vilasi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The cblC disease is an inborn disorder of the vitamin B12 (cobalamin, Cbl) metabolism characterized by methylmalonic aciduria and homocystinuria. The clinical consequences of this disease are devastating and, even when early treated with current therapies, the affected children manifest symptoms involving vision, growth, and learning. The illness is caused by mutations in the gene codifying for MMACHC, a 282aa protein that transports and transforms the different Cbl forms. Here we present data on the structural properties of the truncated protein p.R132X resulting from the c.394C > T mutation that, along with c.271dupA and c.331C > T, is among the most common mutations in cblC. Although missing part of the Cbl binding domain, p.R132X is associated to late-onset symptoms and, therefore, it is supposed to retain residual function. However, to our knowledge structural-functional studies on c.394C > T mutant aimed at verifying this hypothesis are still lacking. By using a biophysical approach including Circular Dichroism, fluorescence, Small Angle X-ray Scattering, and Molecular Dynamics, we show that the mutant protein MMACHC-R132X retains secondary structure elements and remains compact in solution, partly preserving its binding affinity for Cbl. Insights on the fragile stability of MMACHC-R132X-Cbl are provided.

Original languageEnglish
Article number140793
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Issue number6
Publication statusPublished - 1 Jun 2022


  • Methylmalonic aciduria and homocystinuria cblC type
  • MMACHC protein
  • Structure-function relationship
  • Vitamin B12 (cobalamin)

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

Fields of Expertise

  • Human- & Biotechnology


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