Burton Kimberly A, McDermott Deborah A, Wilkes David, Poulsen Melissa N, Nolan Michael A, Goldstein Marc, Basson Craig T, McKnight G Stanley
Department of Pharmacology, University of Washington School of Medicine, Box 357750, Seattle, Washington 98195-7750, USA.
Mol Endocrinol. 2006 Oct;20(10):2504-13. doi: 10.1210/me.2006-0060. Epub 2006 May 25.
Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine tumors. CNC is inherited as an autosomal dominant trait and is transmitted with greater frequency by women vs. men. Nearly two thirds of CNC patients are heterozygous for inactivating mutations in the gene encoding the protein kinase A (PKA) type I alpha regulatory subunit (RI alpha), PRKAR1. We report here that male mice heterozygous for the Prkar1a gene have severely reduced fertility. Sperm from Prkar1a heterozygous mice are morphologically abnormal and reduced in number. Genetic rescue experiments reveal that this phenotype results from elevated PKA catalytic activity in germ cells as early as the pachytene stage of spermatogenesis. Consistent with this defect in the male mutant mice, sperm from CNC patients heterozygous for PRKAR1A mutations were also found to be morphologically aberrant and decreased in number. We conclude that unregulated PKA activity in male meiotic or postmeiotic germ cells leads to structural defects in mature sperm and results in reduced fertility in mice and humans, contributing to the strikingly reduced transmission of PRKAR1A inactivating mutations by male patients with CNC.
卡尼综合征（CNC）是一种家族性多发性肿瘤综合征，其特征为皮肤斑点状色素沉着、心脏和皮肤黏液瘤以及内分泌肿瘤。CNC以常染色体显性性状遗传，女性比男性的传递频率更高。近三分之二的CNC患者在编码蛋白激酶A（PKA）I型α调节亚基（RIα）的基因PRKAR1中存在失活突变的杂合子。我们在此报告，Prkar1a基因杂合的雄性小鼠生育力严重降低。Prkar1a杂合小鼠的精子形态异常且数量减少。基因拯救实验表明，这种表型早在精子发生的粗线期就源于生殖细胞中PKA催化活性的升高。与雄性突变小鼠的这种缺陷一致，还发现PRKAR1A突变杂合的CNC患者的精子形态异常且数量减少。我们得出结论，雄性减数分裂或减数分裂后生殖细胞中不受调控的PKA活性会导致成熟精子出现结构缺陷，并导致小鼠和人类生育力降低，这导致患有CNC的男性患者中PRKAR1A失活突变的传递显著减少。
