A common haplotype containing functional CACNA1H variants is frequently coinherited with increased TPSAB1 copy number

Genet Med. 2018 Apr;20(5):503-512. doi: 10.1038/gim.2017.136. Epub 2017 Sep 21.


PurposeCaV3.2 signaling contributes to nociception, pruritus, gastrointestinal motility, anxiety, and blood pressure homeostasis. This calcium channel, encoded by CACNA1H, overlaps the human tryptase locus, wherein increased TPSAB1 copy number causes hereditary α-tryptasemia. Germ-line CACNA1H variants may contribute to the variable expressivity observed with this genetic trait.MethodsTryptase-encoding sequences at TPSAB1 and TPSB2, and TPSG1 and CACNA1H variants were genotyped in 46 families with hereditary α-tryptasemia syndrome. Electrophysiology was performed on tsA201 HEK cells transfected with wild-type or variant CACNA1H constructs. Effects on clinical phenotypes were interrogated in families with TPSAB1 duplications and in volunteers from the ClinSeq cohort.ResultsThree nonsynonymous variants in CACNA1H (rs3751664, rs58124832, and rs72552056) cosegregated with TPSAB1 duplications in 32/46 families and were confirmed to be in linkage disequilibrium (LD). In vitro, variant CaV3.2 had functional effects: reducing current densities, and altering inactivation and deactivation properties. No clinical differences were observed in association with the CACNA1H haplotype.ConclusionA previously unrecognized haplotype containing three functional CACNA1H variants is relatively common among Caucasians, and is frequently coinherited on the same allele as additional TPSAB1 copies. The variant CACNA1H haplotype, which in vitro imparts partial gain of function, does not result in detectable phenotypic differences in the heterozygous state.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels, T-Type / genetics*
  • Calcium Channels, T-Type / metabolism
  • Cell Line
  • DNA Copy Number Variations*
  • Gene Duplication
  • Gene Frequency*
  • Genetic Association Studies
  • Genetic Loci
  • Genotyping Techniques
  • Haplotypes*
  • Humans
  • Inheritance Patterns*
  • Linkage Disequilibrium
  • Mutation
  • Phenotype
  • Sequence Analysis, DNA
  • Tryptases / genetics*
  • Tryptases / metabolism


  • CACNA1H protein, human
  • Calcium Channels, T-Type
  • TPSAB1 protein, human
  • Tryptases