Zarrilli Federica, Tomaiuolo Rossella, Ceglia Carlo, Lombardo Barbara, Izzo Barbara, Castaldo Giuseppe, Pastore Lucio, De Simone Roberto
*Dipartimento di Bioscienze e Territorio, Università del Molise, Isernia, Italy †Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy §Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, Naples, Italy ∥Dipartimento di Neuroscienze e Scienze Riproduttive e Odontostomatologiche, Università di Napoli Federico II, Naples, Italy ‡CEINGE-Biotecnologie Avanzate, Naples, Italy.
Clin J Pain. 2015 Jan;31(1):52-7. doi: 10.1097/AJP.0000000000000075.
Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results.
We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants.
The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone-degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases.
Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases.
丛集性头痛（CH）的特点是严重、反复发作、单侧发作，疼痛程度剧烈且持续时间短暂。在散发性丛集性头痛患者中对众多基因的变异进行了研究，结果往往相互矛盾。
我们在54例无亲缘关系的散发性丛集性头痛患者以及8个家族中包含更多患病和未患病个体的200名对照者中，研究了一些候选基因，即下丘脑分泌素受体2、生物钟基因（Clock）和乙醇脱氢酶4（ADH4）中的基因突变。此外，我们通过比较基因组杂交进行全基因组扫描，在散发性和家族性丛集性头痛患者及对照者的一个亚组中寻找与DNA增减相关的重排。
对候选基因的分析显示，仅2个ADH4突变的等位基因和基因型频率在散发性丛集性头痛患者和对照者之间存在显著差异；来自2个家族的丛集性头痛患者中这些突变是纯合的。比较基因组杂交分析发现了2个新的重排，分别涉及促甲状腺激素释放激素降解酶和神经纤毛蛋白3（NRXN3）基因的内含子区域。第一种重排在丛集性头痛患者或对照者中均有出现，而第二种仅在一些散发性和家族性丛集性头痛病例中被发现。
我们的数据（尽管来自少数病例）证实了丛集性头痛的遗传异质性，提示ADH4基因的突变以及涉及NRXN3基因的一种新重排在部分病例中可能与丛集性头痛有关。
