Sosero Yuri L, Yu Eric, Estiar Mehrdad A, Krohn Lynne, Mufti Kheireddin, Rudakou Uladzislau, Ruskey Jennifer A, Asayesh Farnaz, Laurent Sandra B, Spiegelman Dan, Trempe Jean-François, Quinnell Timothy G, Oscroft Nicholas, Arnulf Isabelle, Montplaisir Jacques Y, Gagnon Jean-François, Desautels Alex, Dauvilliers Yves, Gigli Gian Luigi, Valente Mariarosaria, Janes Francesco, Bernardini Andrea, Sonka Karel, Kemlink David, Oertel Wolfgang, Janzen Annette, Plazzi Giuseppe, Antelmi Elena, Biscarini Francesco, Figorilli Michela, Puligheddu Monica, Mollenhauer Brit, Trenkwalder Claudia, Sixel-Döring Friederike, Cochen De Cock Valérie, Monaca Christelle Charley, Heidbreder Anna, Ferini-Strambi Luigi, Dijkstra Femke, Viaene Mineke, Abril Beatriz, Boeve Bradley F, Postuma Ronald B, Rouleau Guy A, Ibrahim Abubaker, Stefani Ambra, Högl Birgit, Hu Michele T M, Gan-Or Ziv
Department of Human Genetics, McGill University, Montréal, QC, Canada.
Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
J Parkinsons Dis. 2022;12(1):333-340. doi: 10.3233/JPD-212867.
PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy.
To examine the role of PSAP mutations in iRBD.
We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018).
Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more.
These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
PSAP编码鞘脂激活蛋白C，它是由GBA编码的葡萄糖脑苷脂酶的共激活因子。GBA突变与特发性/孤立性快速眼动睡眠行为障碍（iRBD）有关，iRBD是突触核蛋白病的前驱阶段。
研究PSAP突变在iRBD中的作用。
我们对1113例iRBD患者和2324例对照进行了PSAP全测序，并进行了优化序列核关联测试。我们在3例iRBD患者中鉴定出功能丧失（LoF）突变，PSAP中这种突变非常罕见，而在对照中未发现（未校正p = 0.018）。
两个变异是终止突变，即p.Gln260Ter和p.Glu166Ter，另一个是框内缺失，即p.332_333del。基于计算机分析，所有这三个突变对鞘脂激活蛋白C都有有害影响。此外，p.Glu166Ter和p.332_333del突变的两名携带者还分别携带一个GBA变异，即p.Arg349Ter和p.Glu326Lys。在iRBD队列中，这两个（0.2%）GBA变异携带者中同时出现这些极其罕见的PSAP LoF突变不太可能是偶然发生的（根据gnomAD数据估计在普通人群中的同时发生率为0.00035%）。虽然这3例有PSAP LoF突变的iRBD患者在最后一次随访时均未表型转化为明显的突触核蛋白病，但均表现出提示运动功能障碍的初始迹象，2例被诊断为轻度认知障碍，且均表现出除RBD外的前驱临床标志物。根据运动障碍协会的研究标准，他们前驱期帕金森病的概率为98%或更高。
这些结果表明PSAP变异在iRBD中可能起作用，并与GBA存在潜在的基因相互作用，这需要进一步研究。
