title: Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.
abstract: Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hughes
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Quang T
authors.initials: QT
authors.lastname: Le
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Jamil
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ho
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.affiliation: Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Veterans Affairs Medical Center, San Francisco, California, USA.
authors.forename: Neil N
authors.initials: NN
authors.lastname: Trivedi
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Celeste
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: DiMaggio
authors.affiliation: Clinical Research Directorate/CMRP, SAIC-Frederick, Inc., Frederick National Laboratory for Clinical Research, Frederick, Maryland, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Matthews
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Lewis
authors.affiliation: Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Carlson
authors.affiliation: Institute of Infection, Immunity and Respiratory Medicine, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Peter D
authors.identifier: 0000-0002-7411-5375
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Hong
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sherene
authors.initials: S
authors.lastname: Agama
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Wilson
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sofie
authors.initials: S
authors.lastname: Tucker
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: McElwee
authors.affiliation: National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Maryland
authors.initials: M
authors.lastname: Pao
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Glover
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hohman
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Stone
authors.affiliation: Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Veterans Affairs Medical Center, San Francisco, California, USA.
authors.forename: George H
authors.initials: GH
authors.lastname: Caughey
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Leslie G
authors.identifier: 0000-0002-0197-3811
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Schwartz
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D059350:Chronic Pain / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D003240:Connective Tissue Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004402:Dysautonomia, Familial / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005767:Gastrointestinal Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011537:Pruritus / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D012871:Skin Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D053802:Tryptases / Q000097:blood* / Q000235:genetics*; D055815:Young Adult
chemical_list: C546348:TPSAB1 protein, human; D053802:Tryptases