Some patients with rare genetic diseases (myopathy, neuropathy, ciliopathy, blood diseases) do not have mutations in the known genes and exome or genome sequencing reveals new genetic targets. In our research team, we are using different cell models including yeast Saccharomyces cerevisiaes to validate these new genes and study their variants responsible for rare diseases. The budding yeast Saccharomyces cerevisiae is a unicellular eukaryote with intracellular organization comparable to that of human cells and characterized trafficking and metabolic pathways (Feyder et al, 2015; Kachroo et al, 2015). These mutations often detected in a small number of patients, are the most difficult to validate and an approach starting with the use of the yeast model is not expensive and fast. We are creating humanized yeast cells expressing the human cDNA (tissue-specific isoform) either wild-type or bearing the patient mutation revealed by the sequencing data. Different phenotypes and pathways as membrane trafficking or phosphoinositides lipids levels were analyzed in these humanized yeasts to determine the defects linked to the mutation (Goret et al., 2025; Raess et al., 2017). The yeast model has proven to be very effective so far, as humanization of yeast allowed us to validate new genes in rare diseases and to determine at the cellular level the defects due to the patient mutations.

 

References :

Feyder S, De Craene JO, Bar S, Bertazzi DL, Friant S (2015) Membrane trafficking in the yeast Saccharomyces cerevisiae model. Int J Mol Sci 16: 1509-1525, 10.3390/ijms16011509

Kachroo AH, Laurent JM, Yellman CM, Meyer AG, Wilke CO, Marcotte EM (2015) Systematic humanization of yeast genes reveals conserved functions and genetic modularity. Science 348: 921-925, 10.1126/science.aaa0769

Goret M, Edelweiss E, Jehl J, Reiss D, Aguirre-Pineda P, Friant S, Laporte J. (2025) Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes. Nat Commun 16(1):4667. doi: 10.1038/s41467-025-59925-6.

Raess MA, Cowling BS, Bertazzi DL, Kretz C, Rinaldi B, Xuereb JM, Kessler P, Romero NB, Payrastre B, Friant S, Laporte J. (2017) Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Hum Mol Genet. 26(19):3736. doi: 10.1093/hmg/ddx258.

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