University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Am J Med Genet A. 2011 Sep;155A(9):2170-9. doi: 10.1002/ajmg.a.34167. Epub 2011 Aug 10.
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 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P < 0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium 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.
孤立性马蹄足是一种相对常见的出生缺陷，每年影响美国大约 4000 名新生儿。受影响的腿部（或腿部）的小腿肌肉发育不良，即使经过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足的优先候选风险因素。这一论点进一步得到支持，因为发现编码肌肉收缩复合物成分的基因（MYH3、TPM2、TNNT3、TNNI2 和 MYH8）中的突变导致先天性挛缩，包括远端关节挛缩症（DA）综合征中的马蹄足。在非西班牙裔白人（NHW）和西班牙裔家族的队列中，对编码控制肌纤维收缩性的 15 种基因进行了基因分析，发现 12 种基因中的 SNP 与疾病存在正相关（P < 0.05）；只有 1 个 SNP 在基于家系的验证数据集被识别。在我们的 NHW 发现数据集中，TNNC2 中的 6 个 SNP 偏离 Hardy-Weinberg 平衡。相对风险和似然比检验显示，TNNC2/rs383112 存在母体基因型效应，两个 SNPs（TNNC2/rs4629 和 rs383112）存在遗传/儿童基因型效应。在 NHW 发现数据集中（rs4075583，P = 0.01）、基于家系的验证数据集中（rs1972041，P = 0.000074）和病例对照验证数据集中（rs12148828，P = 0.04），均鉴定出与 TPM1 多个 SNP 的关联。在多个肌肉收缩基因之间发现了基因相互作用，其中许多相互作用涉及至少一个潜在的调节 SNP。总的来说，我们的结果表明，编码骨骼肌肌纤维收缩蛋白的基因变异可能在马蹄足的发病机制中起作用。
