PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum
PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum
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DOI：
10.1093/brain/awt326
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发表时间：
2014-01-01
期刊：
影响因子：
14.5
通讯作者：
Zuechner, Stephan
中科院分区：
文献类型：
--
作者：
Synofzik, Matthis;Gonzalez, Michael A.;Zuechner, Stephan
Boucher-Neuhauser综合征和Gordon Holmes综合征是由早发性共济失调和性腺功能减退加脉络膜视网膜营养不良(Boucher-Neuhauser综合征)或快速反射(Gordon Holmes综合征)定义的临床综合征。在这里，我们揭示了这两个综合征的遗传基础，表明两个临床上不同的实体都是PNPLA6基因隐性突变的等位基因。在7个Boucher-Neuhauser综合征/Gordon Holmes综合征家系中的5个中，我们通过应用整个外显子组测序确定了9个罕见的保守和破坏性突变。此外，通过将Boucher-Neuhauser综合征和Gordon Holmes综合征的复杂临床表现分解为其神经系统组成部分，我们开始分析另外538个来自共济失调(有和没有性腺功能减退)、单纯和复杂遗传性痉挛截瘫以及Charcot-Marie-Tooth病2型的外显子。我们在痉挛共济失调和遗传性痉挛截瘫家系中发现了另外四个PNPLA6突变，揭示了Boucher-Neuhauser和Gordon Holmes综合征实际上代表了由PNPLA6基因突变引起的神经退行性疾病谱上的表型簇。结构分析表明，大多数突变位于磷脂酯酶C末端，可能抑制了PNPLA6的催化活性，为神经递质乙酰胆碱的生物合成提供了前体。我们的研究结果表明，PNPLA6影响多种神经系统，从视网膜到小脑，上下运动神经元和神经内分泌系统，这种蛋白的破坏导致了一系列非常广泛的相关神经退行性疾病。
Boucher-Neuhauser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhauser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhauser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhauser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhauser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.