SMPD1 expression profile and mutation landscape help decipher genotype-phenotype association and precision diagnosis for acid sphingomyelinase deficiency

Hereditas. 2023 Mar 13;160(1):11. doi: 10.1186/s41065-023-00272-1.

PMID: 3690795

Ruisong Wang, Ziyi Qin, Long Huang

Highlights: This 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 Niemann-Pick disease (NPD).

Abstract

Background: A rare genetic disorder called Niemann-Pick disease (NPD), also known as acid sphingomyelinase deficiency (ASMD), is brought on by mutations in the SMPD1 gene, which codes for the enzyme sphingomyelin phosphodiesterase (ASM). Two subtypes of NDP (Type A and B) differ in terms of their dates of start, survival rates, ASM activities, and neurological problems aside from liver and spleen enlargement and lung disease. 144 NPD cases were gathered under stringent quality control using literature mining in order to thoroughly examine the genotype-phenotype connection and pathophysiology features of NPD.

Results: NPD type A can be distinguished from other subtypes of NPD by the difference in ASM activity, with type A having a lower ratio of ASM activity to reference values (threshold of 0.045 (4.45%)). Type A is typically the consequence of quite severe variations like deletions and insertions, which can cause complete loss of ASM function whereas type B is typically the result of relatively modest missense mutations. The p.Arg3AlafsX76 mutation is very common in the Chinese population, and the p.R608del mutation is widespread in Mediterranean nations, according to documented mutations. According to the expression profiles of SMPD1 from GTEx and single-cell RNA sequencing data of multiple fetal tissues, 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. Thus, physicians should pay attention to these organs or tissues when making a diagnosis since SMPD1 deficiency is highly likely to have a major impact on the function of those cell types during development. In addition, 21 more pathogenic mutations were projected in the SMPD1 gene that may result in the NPD, indicating that additional uncommon cases will be found with those SMPD1 mutations. In addition, it is examined how the NPD type A cells responded to the extracellular milieu.

Conclusions: This research is the first to explain how the SMPD1 mutation affects various cell types and tissues, which offers fresh perspectives on the genotype-phenotype relationship and can aid in the accurate diagnosis of NPD.

Keywords: ASMD, Acid sphingomyelinase deficiency, Genotype, Niemann-pick disease type A and B, Novel target for the subtypes, Phenotype