title: Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic "functional" symptomatology including pain, fatigue and gastrointestinal dysmotility.
abstract: Functional disorders are common conditions with a substantial impact on a patients' wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005). Considering a 1-2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Boles
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Hornung
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Alastair E
authors.initials: AE
authors.lastname: Moody
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Ortiz
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Wong
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Eggington
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Stanley
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St, Atlanta, GA 30318, United States.
authors.forename: Mu
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St, Atlanta, GA 30318, United States.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: McLaughlin
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Amir S
authors.initials: AS
authors.lastname: Zare
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Sheldon
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St, Atlanta, GA 30318, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
authors.affiliation: Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McKernan
mesh_terms: D019943:Amino Acid Substitution; D005221:Fatigue / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009325:Nausea / Q000235:genetics*; D010146:Pain / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D018841:HSP90 Heat-Shock Proteins; C092306:TRAP1 protein, human
keywords: Autistic spectrum disorder; Computational protein analysis; Functional disease; Functional medicine; NextGen sequencing; Protein chaperones