Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
BGI-Genomics, BGI-Shenzhen, Shenzhen, China.
Clin Transl Med. 2023 Jun;13(6):e1289. doi: 10.1002/ctm2.1289.
BACKGROUND: HCFC1 encodes transcriptional co-regulator HCF-1, which undergoes an unusual proteolytic maturation at a centrally located proteolysis domain. HCFC1 variants were associated with X-linked cobalamin metabolism disorders and mental retardation-3. This study aimed to explore the role of HCFC1 variants in common epilepsy and the mechanism underlying phenotype heterogeneity. METHODS: Whole-exome sequencing was performed in a cohort of 313 patients with idiopathic partial (focal) epilepsy. Functional studies determined the effects of the variants on the proteolytic maturation of HCF-1, cell proliferation and MMACHC expression. The role of HCFC1 variants in partial epilepsy was validated in another cohort from multiple centers. RESULTS: We identified seven hemizygous HCFC1 variants in 11 cases and confirmed the finding in the validation cohort with additional 13 cases and six more hemizygous variants. All patients showed partial epilepsies with favorable outcome. None of them had cobalamin disorders. Functional studies demonstrated that the variants in the proteolysis domain impaired the maturation by disrupting the cleavage process with loss of inhibition of cell growth but did not affect MMACHC expression that was associated with cobalamin disorder. The degree of functional impairment was correlated with the severity of phenotype. Further analysis demonstrated that variants within the proteolysis domain were associated with common and mild partial epilepsy, whereas those in the kelch domain were associated with cobalamin disorder featured by severe and even fatal epileptic encephalopathy, and those in the basic and acidic domains were associated with mainly intellectual disability. CONCLUSION: HCFC1 is potentially a candidate gene for common partial epilepsy with distinct underlying mechanism of proteolysis dysfunction. The HCF-1 domains played distinct functional roles and were associated with different clinical phenotypes, suggesting a sub-molecular effect. The distinct difference between cobalamin disorders and idiopathic partial epilepsy in phenotype and pathogenic mechanism, implied a clinical significance in early diagnosis and management.
背景：HCFC1 编码转录共调节剂 HCF-1，它在中央位置的蛋白酶结构域经历了一种不寻常的蛋白水解成熟过程。HCFC1 变体与 X 连锁钴胺素代谢紊乱和智力障碍-3 有关。本研究旨在探讨 HCFC1 变体在常见癫痫中的作用及其表型异质性的潜在机制。
方法：对 313 名特发性部分（局灶性）癫痫患者进行全外显子组测序。功能研究确定了变体对 HCF-1 蛋白水解成熟、细胞增殖和 MMACHC 表达的影响。在来自多个中心的另一个队列中验证了 HCFC1 变体在部分性癫痫中的作用。
结果：我们在 11 例患者中发现了 7 种杂合性 HCFC1 变体，并在验证队列中发现了另外 13 例患者和 6 种更多的杂合性变体。所有患者均表现为部分性癫痫，预后良好。他们均无钴胺素紊乱。功能研究表明，蛋白酶结构域中的变体通过破坏切割过程来干扰成熟过程，从而失去对细胞生长的抑制作用，但不影响与钴胺素紊乱相关的 MMACHC 表达。功能损伤程度与表型严重程度相关。进一步分析表明，蛋白酶结构域内的变体与常见的轻度部分性癫痫相关，而 Kelch 结构域内的变体与以严重甚至致命性癫痫性脑病为特征的钴胺素紊乱相关，碱性和酸性结构域内的变体与主要智力障碍相关。
结论：HCFC1 可能是常见部分性癫痫的候选基因，其潜在机制是蛋白水解功能障碍。HCF-1 结构域具有不同的功能作用，与不同的临床表型相关，提示存在亚分子效应。表型和发病机制方面的钴胺素紊乱和特发性部分性癫痫之间的明显差异，暗示了早期诊断和管理的临床意义。
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