Chagay N B, Khayt G Ya, Vdovina T M, Shaforost A A
Stavropol Regional Clinical Consultative and Diagnostic Center; Stavropol State Medical University.
Stavropol Regional Clinical Consultative and Diagnostic Center.
Probl Endokrinol (Mosk). 2021 Mar 30;67(2):28-39. doi: 10.14341/probl12694.
The cystic fibrosis transmembrane regulator (CFTR) gene encodes the synthesis of a protein of the same name, which functions as a direct activator of anionic transport. Chloride is the most abundant anion; as an antagonist of Na+ and K+, it provides electroneutrality of cell membranes at rest; together with cations, it serves as an important osmolyte and forms water flow across cell membranes for transepithelial secretion.Glandular cells in CF trap Cl- and Na+, and the prodused secretion is excessively viscous. Subnormal CFTR activity leads to stagnation of mucociliary clearance, inhibition of intestinal transport.In addition to exocrine disorders, CFTR mutations are associated with a decrease in volume, mass, increased apoptosis of β-cells of the pancreas, a significant suppression of insulin exocytosis in response to stimulation with glucose and glucagon-like peptide-1, hyperglucagonemia against the background of a defect in the suppression of α-cell function by insulin, but a decrease in maximum capacity α-cells.Deficiency and progressive decline in bone mineral density is an expected secondary manifestation of CF due to pancreatic exocrine insufficiency with malabsorption of nutrients and fat-soluble vitamins. However, in patients with the F508del mutation, a significant decrease in the synthesis of OPG, COX-2, PGE2 in the osteoblastic formation, and an increase in the activity of the antianabolic NF-kB were found. We are talking about a defect in the canonical signaling pathway (Wnt/β-catenin), which regulates the expression of genes-activators of osteoblastogenesis, dissociation of the stages of physiological bone remodeling.In addition to congenital bilateral or unilateral aplasia of the vas deferens, an increase in the frequency of CFTR mutations is also found in non-obstructive azoospermia, oligo-, astheno- and teratospermia. CFTR is involved in the entry of HCO3- into Sertoli cells to trigger cAMP-dependent transcription and its defects lead to suppression of FSH-dependent gene expression of spermatogenesis, loss of sequence in the Wnt cascade, destruction of the PGE2-dependent transepithelial interaction and, as a consequence, the blood-testicular barrier.CF is characterized, along with classical signs, by endocrine dysfunction of the pancreas, osteoporosis with suppression of osteoblastogenesis, and a defect in spermatogenesis.
囊性纤维化跨膜传导调节因子(CFTR)基因编码合成同名蛋白质,该蛋白质作为阴离子转运的直接激活剂发挥作用。氯离子是最丰富的阴离子;作为Na+和K+的拮抗剂,它在静息状态下维持细胞膜的电中性;与阳离子一起,它作为重要的渗透溶质,形成跨细胞膜的水流以进行上皮分泌。CF患者的腺细胞会捕获Cl-和Na+,产生的分泌物异常黏稠。CFTR活性低下会导致黏液纤毛清除功能停滞,肠道运输受到抑制。除了外分泌紊乱,CFTR突变还与胰腺β细胞体积减小、质量减轻、凋亡增加,对葡萄糖和胰高血糖素样肽-1刺激的胰岛素胞吐作用显著抑制,胰岛素对α细胞功能抑制缺陷背景下的高胰高血糖素血症,但α细胞最大容量降低有关。骨矿物质密度不足和逐渐下降是CF的预期继发表现,这是由于胰腺外分泌功能不全导致营养物质和脂溶性维生素吸收不良。然而,在携带F508del突变的患者中,发现成骨细胞形成过程中骨保护素(OPG)、环氧化酶-2(COX-2)、前列腺素E2(PGE2)的合成显著减少,而促分解代谢的核因子κB(NF-κB)活性增加。这涉及经典信号通路(Wnt/β-连环蛋白)的缺陷,该通路调节成骨细胞生成基因激活剂的表达,破坏生理性骨重塑阶段的解离。除了先天性双侧或单侧输精管发育不全,在非梗阻性无精子症、少精子症、弱精子症和畸形精子症中也发现CFTR突变频率增加。CFTR参与HCO3-进入支持细胞以触发cAMP依赖性转录,其缺陷会导致抑制FSH依赖性精子发生基因表达、Wnt级联序列缺失、破坏PGE2依赖性跨上皮相互作用,进而导致血睾屏障受损。CF的特征除了经典症状外,还包括胰腺内分泌功能障碍、抑制成骨细胞生成的骨质疏松症以及精子发生缺陷。