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

Abstract

Background 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. Results 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. Conclusions 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.

Allele frequency of pathogenic variants causing acid sphingomyelinase deficiency and Gaucher disease in the general Japanese population

“…The most common variant type was missense—16 of 24 SMPD1 variants (66.7%) and 22 of 29 GBA1 variants (75.9%). Pathogenic SMPD1 variants that are commonly reported worldwide, including p.Arg610del, p.Arg498Leu, and p.Phe333Serfs*52, were not included in jMorp 8 , 9 . Patients with mild forms of ASMD can have a natural history of morbidity extending into their 60s 10 .…”

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

“…The severity of symptoms in carriers can vary, and this phenomenon is often referred to as "carrier or heterozygote manifestations". It means that, in some genetic disorders, individuals with only one copy of the mutated gene may show milder forms of the condition or may have subtle symptoms [4].…”

ASM Variants in the Spotlight: A Structure-Based Atlas for Unraveling Pathogenic Mechanisms in Lysosomal Acid Sphingomyelinase

“…We collected variants from literature starting from two recent publications 5,17 and including additional variants reported in Uniprot (Uniprot entry P17405). We retained only missense mutations in the coding region and removed cases of multiple mutations.…”

“…Recently, an approach based on different sequence and structural features has been used to classify ASM variants 15 . In another study, one of the recent models for predicting pathogenicity based on evolutionary-related properties, i.e., EVE 16 was applied to study a group of variants from SMPD1 17 . However, the aforementioned studies do not directly link to the underlying molecular mechanisms exerted by the mutations.…”