We have previously reported a novel homozygous 4-bp deletion in DDHD1 as the responsible variant for spastic paraplegia type 28 (SPG28;OMIM#609340). The variant causes a frameshift, resulting in a functionally null allele in the patient. DDHD1 encodes phospholipase A1 (PLA1) catalyzing phosphatidylinositol to lysophosphatidylinositol (LPI). To clarify the pathogenic mechanism of SPG28, we established Ddhd1 knockout mice (Ddhd1[-/-]) carrying a 5-bp deletion in Ddhd1, resulting in a premature termination of translation at a position similar to that of the patient. We observed a significant decrease in foot-base angle (FBA) in aged Ddhd1(-/-) (24 months of age) and a significant decrease of LPI 20:4 (sn-2) in Ddhd1(-/-) cerebra (26 months of age). These changes of FBA were not observed in 14 months of age. We also observed significant changes of expression levels of 22 genes in the Ddhd1(-/-) cerebra (26 months of age). GO terms relating to the nervous system and cell-cell communications were significantly enriched. We conclude that the reduced signaling of LPI 20:4 (sn-2) by PLA1 dysfunction is responsible for the locomotive abnormality in SPG28, further suggesting that the reduction of downstream signaling such as GPR55 which is agonized by LPI is involved in the pathogenesis of SPG28.

中文翻译：

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Ddhd1 基因敲除小鼠作为家族性痉挛性截瘫的运动和生理异常模型。

我们之前曾报道过 DDHD1 中的一个新的纯合 4-bp 缺失是 28 型痉挛性截瘫（SPG28；OMIM#609340）的负责变异。该变体导致移码，导致患者的功能无效等位基因。DDHD1 编码将磷脂酰肌醇催化为溶血磷脂酰肌醇 (LPI) 的磷脂酶 A1 (PLA1)。为了阐明 SPG28 的致病机制，我们建立了 Ddhd1 基因敲除小鼠 (Ddhd1[-/-])，在 Ddhd1 中携带 5-bp 缺失，导致翻译在与患者相似的位置过早终止。我们观察到老年 Ddhd1(-/-)（24 个月大）的足底角 (FBA) 显着降低，而 Ddhd1(-/-) 大脑的 LPI 20:4 (sn-2) 显着降低（ 26 个月大）。在 14 个月大时未观察到 FBA 的这些变化。我们还观察到 Ddhd1(-/-) 大脑（26 个月大）中 22 个基因表达水平的显着变化。与神经系统和细胞间通讯相关的 GO 术语显着丰富。我们得出结论，PLA1 功能障碍导致 LPI 20:4 (sn-2) 信号减少是 SPG28 机车异常的原因，进一步表明下游信号的减少，如受 LPI 激动的 GPR55 参与了 LPI 的发病机制SPG28。