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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 ?-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 ?-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 ?-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.

SUBMITTER: Lyons JJ

PROVIDER: S-EPMC5397297 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Lyons Jonathan J JJ Yu Xiaomin X Hughes Jason D JD Le Quang T QT Jamil Ali A Bai Yun Y Ho Nancy N Zhao Ming M Liu Yihui Y O'Connell Michael P MP Trivedi Neil N NN Nelson Celeste C DiMaggio Thomas T Jones Nina N Matthews Helen H Lewis Katie L KL Oler Andrew J AJ Carlson Ryan J RJ Arkwright Peter D PD Hong Celine C Agama Sherene S Wilson Todd M TM Tucker Sofie S Zhang Yu Y McElwee Joshua J JJ Pao Maryland M Glover Sarah C SC Rothenberg Marc E ME Hohman Robert J RJ Stone Kelly D KD Caughey George H GH Heller Theo T Metcalfe Dean D DD Biesecker Leslie G LG Schwartz Lawrence B LB Milner Joshua D JD

Nature genetics 20161017 12

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 germlin ...[more]

PMID: 27749843

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Project description:Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10-6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman's r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

Dataset Information

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

Publications

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

Similar Datasets

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