College of Life and Environmental Sciences, Hunan University of Arts and Science, 3150 Dongting Ave., Changde, 415000, Hunan Province, People's Republic of China.
Affiliated Hospital of Hunan University of Arts and Science (the Maternal and Child Health Hospital), Medical college, 3150 Dongting Ave., Changde, Hunan Province, People's Republic of China, 415000.
Hereditas. 2023 Mar 13;160(1):11. doi: 10.1186/s41065-023-00272-1.
Acid sphingomyelinase deficiency (ASMD) disorder, also known as Niemann-Pick disease (NPD) is a rare genetic disease caused by mutations in SMPD1 gene, which encodes sphingomyelin phosphodiesterase (ASM). Except for liver and spleen enlargement and lung disease, two subtypes (Type A and B) of NDP have different onset times, survival times, ASM activities, and neurological abnormalities. To comprehensively explore NPD's genotype-phenotype association and pathophysiological characteristics, we collected 144 NPD cases with strict quality control through literature mining.
The difference in ASM activity can differentiate NPD type A from other subtypes, with the ratio of ASM activity to the reference values being lower in type A (threshold 0.045 (4.45%)). Severe variations, such as deletion and insertion, can cause complete loss of ASM function, leading to type A, whereas relatively mild missense mutations generally result in type B. Among reported mutations, the p.Arg3AlafsX76 mutation is highly prevalent in the Chinese population, and the p.R608del mutation is common in Mediterranean countries. The expression profiles of SMPD1 from GTEx and single-cell RNA sequencing data of multiple fetal tissues showed that high expressions of SMPD1 can be observed in the liver, spleen, and brain tissues of adults and hepatoblasts, hematopoietic stem cells, STC2_TLX1-positive cells, mesothelial cells of the spleen, vascular endothelial cells of the cerebellum and the cerebrum of fetuses, indicating that SMPD1 dysfunction is highly likely to have a significant effect on the function of those cell types during development and the clinicians need pay attention to these organs or tissues as well during diagnosis. In addition, we also predicted 21 new pathogenic mutations in the SMPD1 gene that potentially cause the NPD, signifying that more rare cases will be detected with those mutations in SMPD1. Finally, we also analysed the function of the NPD type A cells following the extracellular milieu.
Our study is the first to elucidate the effects of SMPD1 mutation on cell types and at the tissue level, which provides new insights into the genotype-phenotype association and can help in the precise diagnosis of NPD.
酸性鞘磷脂酶缺乏症（ASMD），也称为尼曼-匹克病（NPD），是一种由 SMPD1 基因突变引起的罕见遗传性疾病，该基因编码鞘磷脂磷酸二酯酶（ASM）。除了肝脾肿大和肺部疾病外，两种亚型（A 型和 B 型）的 NPD 具有不同的发病时间、生存时间、ASM 活性和神经异常。为了全面探讨 NPD 的基因型-表型相关性和病理生理特征，我们通过文献挖掘收集了 144 例经过严格质量控制的 NPD 病例。
ASM 活性的差异可将 NPD 型 A 与其他亚型区分开来，型 A 的 ASM 活性与参考值的比值较低（阈值 0.045（4.45%））。严重的变异，如缺失和插入，可导致完全丧失 ASM 功能，导致 A 型，而相对温和的错义突变通常导致 B 型。在报道的突变中，p.Arg3AlafsX76 突变在中国人群中高度流行，p.R608del 突变在地中海国家中常见。来自 GTEx 的 SMPD1 表达谱和多胎组织的单细胞 RNA 测序数据表明，成人和胎肝细胞、造血干细胞、STC2_TLX1 阳性细胞、脾间皮细胞、小脑和大脑血管内皮细胞中 SMPD1 高表达，表明 SMPD1 功能障碍极有可能对发育过程中这些细胞类型的功能产生重大影响，临床医生在诊断时也需要注意这些器官或组织。此外，我们还预测了 SMPD1 基因中的 21 个新的潜在致病性突变，这些突变可能导致 NPD，这表明将检测到更多的罕见病例。最后，我们还分析了细胞外环境对 NPD 型 A 细胞功能的影响。
我们的研究首次阐明了 SMPD1 突变对细胞类型和组织水平的影响，为基因型-表型相关性提供了新的见解，并有助于 NPD 的精确诊断。
