title: HSP90 Shapes the Consequences of Human Genetic Variation.
abstract: HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: gkarras@wi.mit.edu.
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Karras
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yi
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Máté
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Center for DNA Damage and Repair and Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Center for DNA Damage and Repair and Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: whitesell@wi.mit.edu.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D052217:Fanconi Anemia Complementation Group A Protein / Q000737:chemistry / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D013312:Stress, Physiological; D014430:Twins, Monozygotic
chemical_list: C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins
keywords: Fanconi anemia; HSP70; HSP90 buffering; cancer; gene-environment interaction