Characterization of the chromosome 4 genes that affect fluconazole-induced disomy formation in Cryptococcus neoformans
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Heteroresistance in Cryptococcus neoformans is an intrinsic adaptive resistance to azoles and the heteroresistant phenotype is associated with disomic chromosomes. Two chromosome 1 (Chr1) genes, ERG11, the fluconazole target, and AFR1, a drug transporter, were reported as major factors in the emergence of Chr1 disomy. In the present study, we show Chr4 to be the second most frequently formed disomy at high concentrations of fluconazole (FLC) and characterize the importance of resident genes contributing to disomy formation. We deleted nine Chr4 genes presumed to have functions in ergosterol biosynthesis, membrane composition/integrity or drug transportation that could influence Chr4 disomy under FLC stress. Of these nine, disruption of three genes homologous to Sey1 (a GTPase), Glo3 and Gcs2 (the ADP-ribosylation factor GTPase activating proteins) significantly reduced the frequency of Chr4 disomy in heteroresistant clones. Furthermore, FLC resistant clones derived from sey1Δglo3Δ did not show disomy of either Chr4 or Chr1 but instead had increased the copy number of the genes proximal to ERG11 locus on Chr1. Since the three genes are critical for the integrity of endoplasmic reticulum (ER) in Saccharomyces cerevisiae, we used Sec61ß-GFP fusion as a marker to study the ER in the mutants. The cytoplasmic ER was found to be elongated in sey1Δ but without any discernable alteration in gcs2Δ and glo3Δ under fluorescence microscopy. The aberrant ER morphology of all three mutant strains, however, was discernable by transmission electron microscopy. A 3D reconstruction using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) revealed considerably reduced reticulation in the ER of glo3Δ and gcs2Δ strains. In sey1Δ, ER reticulation was barely detectable and cisternae were expanded extensively compared to the wild type strains. These data suggest that the genes required for maintenance of ER integrity are important for the formation of disomic chromosomes in C. neoformans under azole stress.
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Antifungal heteroresistance refers to the coexistence of a small population of resistant cells, usually much less than 1%, and a large population of susceptible fungal cells.
“Antifungal heteroresistance refers to the coexistence of a small population of resistant cells (usually <<1%) and a large population of susceptible fungal cells (Fig 1).”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [27]
The Introduction (page not specified) describes minor resistant subpopulations emerging within a susceptible C. neoformans colony, supporting the coexistence described. Neither it nor the Results (page not specified) gives a frequency of usually much less than 1%, and the paper discusses this phenotype specifically in Cryptococcus rather than defining it across all fungi. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAntifungal heteroresistance was first found in C. neoformans and Cryptococcus gattii and is considered an intrinsic property of these species, associated with disomic chromosomes.
“Antifungal heteroresistance was first been found in C. neoformans and Cryptococcus gattii, and was considered as an intrinsic property of these species, associating with disomic chromosomes [24–27].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [27]
The Introduction reports heteroresistance in C. neoformans in 1999 and describes it as intrinsic in both C. neoformans and C. gattii. The Abstract and Introduction link heteroresistance to disomic chromosomes in C. neoformans, but the supplied passages do not establish that association in C. gattii. Page numbers are not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIf any of the ERG11, SEY1, GCS2 or GLO3 genes are relocated to chr3, then the frequency of chr3 disomy could increase.
“If any of the ERG11, SEY1, GCS2 or GLO3 genes are relocated to chr3, then the frequency of chr3 disomy could increase [143,144].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [143]
The Results section on relocation to Chr3 reports increased Chr3 disomy after SEY1 or GLO3 was inserted there, and cites ERG11 relocation as a similar example. The paper links GCS2 deletion to Chr4 disomy, but does not report relocating GCS2 to Chr3 or an effect on Chr3 disomy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA high incidence of chr4 disomy may be related to SEY1, GCS2 or GLO3 genes.
“Ngamskulrungroj et al. demonstrated a high incidence of chr4 disomy, which may be related to SEY1 (GTPase with a role in Endoplasmic Reticulum morphology), GCS2 (ADP-ribosylation factor GTPase activating proteins) or GLO3 (ADP-ribosylation factor GTPase activating proteins) genes [143].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [143]
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The Influence of Genetic Stability onAspergillus fumigatusVirulence and Azole Resistance
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The influence of genetic stability on Aspergillus fumigatus virulence and azole resistance
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- Authors
- Ngamskulrungroj, P., Chang, Y., Hansen, B., Bugge, C., Fischer, E., & Kwon-Chung, K. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kwon-Chung, Kyung J.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-03-07
- Volume
- 7
- Issue
- 3
- Pages
- e33022
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3296764
- OpenAlex
- W2034592203
- Cited by
- 56
- References
- 61
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 1 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 2
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- NHLBI Division of Intramural Research
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Cryptococcus neoformans, fluconazole, heteroresistance, azole resistance, ERG11
- MeSH terms
- Antifungal Agents, Cryptococcus neoformans, Drug Tolerance, Endoplasmic Reticulum, Genes, Fungal, Translocation, Genetic, Fluconazole, Chromosomes, Fungal, Gene Deletion, Uniparental Disomy, Drug Resistance, Fungal, Chromosome Duplication
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