Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis
Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis
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DOI：
10.1002/humu.24315
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发表时间：
2021-12-28
期刊：
影响因子：
3.9
通讯作者：
Ferec, Claude
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Masson, Emmanuelle;Ferec, Claude
最近发现TRPV 6作为胰腺炎易感基因，用于确定慢性胰腺炎（CP）的新机制，由于Ca 2+失调。在此，我们通过靶向下一代测序分析了81例遗传性CP（HCP）先证者、204例家族性CP（FCP）先证者和462例特发性CP（ICP）患者的TRPV 6。我们鉴定了25种罕见的非同义TRPV 6变异体，其中18种以前从未报道过。所有18种变体的特征在于通过Ca 2+成像测定，其中8种被鉴定为功能缺陷。在三个CP群组中对功能缺陷变体的评估揭示了两个新的发现：（i）与ICP患者相比，HCP/FCP患者中功能缺陷TRPV 6变体似乎更频繁地出现，（3.2%对1.5%）和（ii）在HCP和FCP先证者中发现的功能缺陷TRPV 6变体似乎更频繁地与SPINK 1，CTRC，和（或）CFTR高于ICP组（66.7%比28.6%）。此外，可用的HCP和FCP家族成员的遗传分析揭示了复杂的遗传模式，在一些家庭。我们的研究结果证实，功能缺陷的TRPV 6变体是CP的重要贡献者。重要的是，功能缺陷的TRPV 6变体占HCP/FCP病例的很大比例。
The recent discovery of TRPV6 as a pancreatitis susceptibility gene served to identify a novel mechanism of chronic pancreatitis (CP) due to Ca2+ dysregulation. Herein, we analyzed TRPV6 in 81 probands with hereditary CP (HCP), 204 probands with familial CP (FCP), and 462 patients with idiopathic CP (ICP) by targeted next-generation sequencing. We identified 25 rare nonsynonymous TRPV6 variants, 18 of which had not been previously reported. All 18 variants were characterized by a Ca2+ imaging assay, with 8 being identified as functionally deficient. Evaluation of functionally deficient variants in the three CP cohorts revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Our findings confirm that functionally deficient TRPV6 variants represent an important contributor to CP. Importantly, functionally deficient TRPV6 variants account for a significant proportion of cases of HCP/FCP.