Format

Send to

Choose Destination
Nat Genet. 2016 Dec;48(12):1564-1569. doi: 10.1038/ng.3696. Epub 2016 Oct 17.

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.

Author information

1
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
2
Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.
3
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
4
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
5
Research Technologies Branch, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA.
6
Cardiovascular Research Institute and Department of Medicine, University of California at San Francisco, San Francisco, California, USA.
7
Veterans Affairs Medical Center, San Francisco, California, USA.
8
Clinical Research Directorate/CMRP, SAIC-Frederick, Inc., Frederick National Laboratory for Clinical Research, Frederick, Maryland, USA.
9
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
10
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
11
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.
12
Institute of Infection, Immunity and Respiratory Medicine, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
13
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
14
National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, USA.
15
Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA.
16
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

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.

PMID:
27749843
PMCID:
PMC5397297
DOI:
10.1038/ng.3696
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center