Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Department of Physiology & Pharmacology, Faculty of Medicine, and The Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Genet Med. 2018 Apr;20(5):503-512. doi: 10.1038/gim.2017.136. Epub 2017 Sep 21.
PurposeCa3.2 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 Ca3.2 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.
Ca3.2 信号传导有助于痛觉、瘙痒、胃肠蠕动、焦虑和血压稳态。这种钙通道由 CACNA1H 编码，与人类组织蛋白酶 S 基因座重叠，其中 TPSAB1 拷贝数的增加导致遗传性 α-组织蛋白酶血症。胚系 CACNA1H 变体可能导致该遗传特征的表现型变异性。
对 46 个遗传性 α-组织蛋白酶血症综合征家族的 TPSAB1 和 TPSB2、TPSG1 和 CACNA1H 变体的编码序列进行基因分型。在转染野生型或变体 CACNA1H 构建体的 tsA201 HEK 细胞上进行电生理学实验。在 TPSAB1 重复家族和 ClinSeq 队列中的志愿者中，研究了对临床表型的影响。
在 32/46 个家族中，CACNA1H 中的三个非同义变体（rs3751664、rs58124832 和 rs72552056）与 TPSAB1 重复共分离，并证实它们处于连锁不平衡（LD）状态。体外实验显示，变体 Ca3.2 具有功能效应：降低电流密度，并改变失活和去激活特性。与 CACNA1H 单倍型相关的临床差异未观察到。
一个以前未被识别的包含三个功能性 CACNA1H 变体的单倍型在白种人中相对常见，并且经常与额外的 TPSAB1 拷贝一起在同一等位基因上共遗传。体外赋予部分功能获得的变体 CACNA1H 单倍型不会导致杂合状态下可检测的表型差异。
