Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot.
Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot.
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DOI：
10.1002/ajmg.a.34167
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发表时间：
2011-09
影响因子：
2
通讯作者：
Hecht, Jacqueline T.
中科院分区：
文献类型：
--
作者：
Weymouth, Katelyn S.;Blanton, Susan H.;Bamshad, Michael J.;Beck, Anita E.;Alvarez, Christine;Richards, Steve;Gurnett, Christina A.;Dobbs, Matthew B.;Barnes, Douglas;Mitchell, Laura E.;Hecht, Jacqueline T.
孤立性马蹄内翻足是一种相对常见的出生缺陷，每年影响美国约 4,000 名新生儿。受影响腿部的小腿肌肉发育不全，即使在矫正治疗后仍然很小。这一观察结果表明，影响肌肉发育的基因变异是马蹄内翻足的优先候选危险因素。这一论点得到了以下发现的进一步支持：编码肌肉收缩复合体（MYH3、TPM2、TNNT3、TNNI2 和 MYH8）成分的基因突变会导致远端关节挛缩 (DA) 综合征中的先天性挛缩，包括马蹄内翻足。在一组非西班牙裔白人 (NHW) 和西班牙裔家族中，对编码控制肌纤维收缩性的蛋白质的 15 个基因进行询问，发现 12 个基因与 SNP 呈正相关 (p<0.05)；在基于家庭的验证数据集中仅识别出一个。在我们的 NHW 发现数据集中，TNNC2 中的 6 个 SNP 偏离母亲的哈迪温伯格平衡 (HWE)。相对风险和似然比测试显示，TNNC2/rs383112 具有母体基因型效应，TNNC2/rs4629 和 rs383112 两个 SNP 具有遗传/儿童基因型效应。在 NHW 发现（rs4075583，p=0.01）、基于家族的验证（rs1972041，p=0.000074）和病例对照验证（rs12148828，p=0.04）数据集中确定了与 TPM1 中多个 SNP 的关联。多个肌肉收缩基因之间的基因相互作用被确定，其中许多相互作用涉及至少一种潜在的调节性 SNP。总的来说，我们的结果表明，编码骨骼肌纤维收缩蛋白的基因变异可能在马蹄足的病因学中发挥作用。
Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of fifteen genes encoding proteins that control myofiber contractility in a cohort of both nonHispanic white (NHW) and Hispanic families, identified positive associations (p<0.05) with SNPs in twelve genes; only one was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy Weinberg Equilibrium (HWE) in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, p=0.01), family-based validation (rs1972041, p=0.000074) and case-control validation (rs12148828, p=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.
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影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR
DOI：
10.1302/0301-620x.76b3.8175852
发表时间：
1994-05-01
影响因子：
--
作者：
FUKUHARA, K;SCHOLLMEIER, G;UHTHOFF, HK
通讯作者：
UHTHOFF, HK
影响因子：
2.1
作者：
Komar, Anton A.
通讯作者：
Komar, Anton A.
影响因子：
2
作者：
Blanton, SH;Cortez, A;Hecht, JT
通讯作者：
Hecht, JT
影响因子：
4.2
作者：
Ester, Audrey R.;Yerman, Gayle;Hecht, Jacqueline T.
通讯作者：
Hecht, Jacqueline T.