NEJM：研究揭示共济失调、痴呆和低性腺功能综合征的致病基因

一例共济失调、痴呆和低性腺功能综合征患者的影像学及神经病理资料

共济失调和性腺机能减退综合征在一个世纪以前就被描述，但是其基因异常情况却不甚明了。来自哈佛生殖研究中心的David H. Margolin等教授采用外显子测序的方法揭示了共济失调、痴呆和低性腺功能综合征的致病基因，发现其与泛素化功能障碍相关，研究结果在线发表在新英格兰杂志上。

该研究采用全外显子测序的方法检测了伴有共济失调及低促性腺激素性腺功能减退一例患者，然后在同样受影响的患者中进行候选基因的靶向测序。详细记录神经及生殖内分泌表型的特点。在斑马鱼模型中检测了突变序列与表观遗传的交互作用。

在有血缘关系的亲属中发现RNF216和OTUD4双基因纯合子突变，他们分别编码泛素化的E3和去泛素化酶。另外在一例不相关的患者中发现复合杂合子截断突变，在4例其他患者中发现单杂合子有害突变。基因敲除斑马鱼胚胎的rnf216或otud4基因，产生眼睛、视顶盖和小脑的缺陷；同时敲除两基因这些症状表型加重，非突变基因可以逆转，但人类RNF216或 OTUD4及信使RNA却不可以。所有患者有进行性加重的共济失调和痴呆。在小脑传导路及海马中可见明显神经损失，存活的海马神经元内可见泛素免疫反应性的细胞核内包涵体。在生殖内分泌轴的下丘脑和垂体水平检测出明显缺陷。

低促性腺激素性腺功能减退、共济失调和痴呆综合征由RNF216基因突变或RNF216和OTUD4联合突变所致。这些结果显示泛素化障碍与神经变性及生殖障碍间的关系，而且再次验证了外显子测序在揭示致病基因相互作用的功能研究中的巨大潜力。

与致病基因相关的拓展阅读：

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Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination.
Abstract
Background The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. Methods We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. Results Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. Conclusions The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).