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

作者：Lyons Jonathan J; Stotz Stephanie C; Chovanec Jack; Liu Yihui; Lewis Katie L; Nelson Celeste; DiMaggio Thomas; Jones Nina; Stone Kelly D; Sung Heejong; Biesecker Leslie G; Colicos Michael A; Milner Joshua D^*

来源：Genetics in Medicine, 2018, 20(5): 503-512.

DOI：10.1038/gim.2017.136

• CACNA1H
• hereditary alpha-tryptasemia
• tryptase
• Ca(V)3.2

Purpose: Ca(V)3.2 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 alpha-tryptasemia. Germ-line CACNA1H variants may contribute to the variable expressivity observed with this genetic trait.
Methods: Tryptase-encoding sequences at TPSAB1 and TPSB2, and TPSG1 and CACNA1H variants were genotyped in 46 families with hereditary alpha-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.
Results: Three 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 Ca(V)3.2 had functional effects: reducing current densities, and altering inactivation and deactivation properties. No clinical differences were observed in association with the CACNA1H haplotype.
Conclusion: A 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.

• 出版日期2018-5
• 单位NIH