Laboratory of Human Genetics of Neurological Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Brain. 2017 Mar 1;140(3):555-567. doi: 10.1093/brain/aww343.
Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.
瘙痒被认为代表了通过激活特定神经元和受体与疼痛共享的躯体感觉通路所传递的刺激的特殊反应。它可以与皮肤病、系统性和神经疾病有关，也可以是某些药物的副作用。然而，一些患者患有慢性特发性瘙痒，这种瘙痒通常归因于心理困扰，目前尚无生物标志物。我们调查了三个多代家族，其中一个家族被诊断为关节过度活动综合征/埃勒斯-当洛斯综合征过度活动型（JHS/EDS-HT），其特征是特发性慢性瘙痒，主要分布在近端。对所有 8 名受影响的成员进行了皮肤活检，其中 6 名成员的表皮内神经纤维密度降低，符合小纤维神经病。全外显子组测序发现两个 COL6A5 罕见变异与 8 名受影响成员的慢性瘙痒共分离，在非受影响成员和一名无关的散发性 1 型无痛性糖尿病性神经病和慢性瘙痒患者中不存在。两个家族和糖尿病患者携带无义 c.6814G>T（p.Glu2272*）变异，另一个家族携带错义 c.6486G>C（p.Arg2162Ser）变异。两种变异的计算机分析预测为可能的致病性。这两种变异在 6271 名健康对照者中的频率较低（次要等位基因频率<0.1%），在 77 名小纤维神经病患者和 167 名无瘙痒的 JHS/EDS-HT 患者中均不存在。对携带无义变异的两个家族患者成纤维细胞的 cDNA 进行的无效等位基因测试表明，由于无义介导的 RNA 衰变的激活，功能半合子不足。免疫荧光显微镜和 Western blot 分别显示出明显的组织紊乱和 COL6A5 合成减少。间接免疫荧光显示，携带无义变异的患者皮肤中 COL6A5 表达减少。加巴喷丁类药物治疗为携带突变的患者提供了令人满意的瘙痒缓解。我们的发现首次揭示了 COL6A5 基因与家族性慢性瘙痒之间的关联，提示神经病理性瘙痒发病机制的新贡献因素，并确定了新的候选治疗靶点。
