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Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number
Jonathan J Lyons1, Xiaomin Yu1, Jason D Hughes2
1Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Nature Genetics
|November 8, 2016
Summary
Genetic duplications in the TPSAB1 gene cause elevated serum tryptase, leading to multisystem symptoms like irritable bowel syndrome and dysautonomia. This discovery reveals a gene-dose effect impacting symptom severity.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Elevated basal serum tryptase affects 4-6% of the population with unknown causes.
- Previous studies identified inherited elevated tryptase linked to multisystem complaints.
Purpose of the Study:
- Identify the genetic basis for inherited elevated basal serum tryptase.
- Correlate genetic findings with multisystem symptom complexes.
Main Methods:
- Genetic analysis of 35 families with inherited elevated tryptase.
- Sequencing of the TPSAB1 gene.
- Analysis of two additional cohorts (172 individuals).
Main Results:
- Germline duplications and triplications in TPSAB1 identified.
- Higher α-tryptase gene copy numbers correlated with increased tryptase levels and symptom severity (gene-dose effect).
- Elevated serum tryptase exclusively associated with TPSAB1 sequence duplication in additional cohorts.
Conclusions:
- TPSAB1 duplications are linked to inherited elevated basal serum tryptase.
- These duplications are associated with multisystem complaints including IBS, cutaneous issues, dysautonomia, and connective tissue abnormalities.
