Novel mutations in the SMPD1 gene in Jordanian children with Acid sphingomyelinase deficiency (Niemann-Pick types A and B)

AL-Eitan, Laith N.; Alqa'qa', Kifah; Amayreh, Wajdi; Aljamal, Hanan A.; Khasawneh, Rame; Al-Zoubi, Batool; Okour, Israa; Haddad, Amany; Haddad, Yazan; Haddad, Hazem

doi:10.1016/j.gene.2020.144683

Cited by 5 publications

(1 citation statement)

References 33 publications

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“…Acid sphingomyelinase (ASM; EC 3.1.4.12) hydrolyzes the membrane lipid sphingomyelin to phosphorylcholine and bioactive lipid ceramide. Variants in the sphingomyelin phosphodiesterase 1 ( SMPD1 ) gene lead to the type A and B forms of lysosomal storage disorder NPD [ 1 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

SMPD1 gene variants in patients with β-Thalassemia major

Dursun

Özen

2023

Mol Biol Rep

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Background β-thalassemia major and Niemann-Pick diseases have similar clinical and laboratory findings. We aimed to investigate the effects of sphingomyelin phosphodiesterase 1 (SMPD1) gene variants on the clinical and laboratory findings in patients with β-thalassemia major. Methods and results This study included 45 patients who were followed up for β-thalassemia major in our clinic. Plasma chitotriosidase, leukocyte acid sphingomyelinase, liver enzymes, ferritin, hemogram, biochemical parameters, SMPD1 gene variant analysis, cardiac T2* MRI, and liver R2 MRI were assessed in all patients. The SMPD1 gene c.132_143del, p.A46_L49del (c.108GCTGGC[4] (p.38AL[4])) (rs3838786) variant was detected in 9 of 45 (20.0%) patients. Plasma chitotriosidase, ferritin, acetyl aminotransferase, and alanine aminotransferase levels were significantly higher in patients with the gene variant than in those without (p < 0.05). Leukocyte acid sphingomyelinase levels were significantly lower in patients with the gene variant than in those without (p < 0.05). Conclusion These results imply that the clinical and laboratory findings and some features of disease progression in patients with β-thalassemia major are similar to those of Niemann-Pick disease. They also suggest that SMPD1 gene c.132_143del, p.A46_L49del (c.108GCTGGC[4] (p.38AL[4])) (rs3838786) variant may underlie these clinical findings in patients with β-thalassemia major.

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Section: Introductionmentioning

confidence: 99%

SMPD1 gene variants in patients with β-Thalassemia major

Dursun

Özen

2023

Mol Biol Rep

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

et al. 2023

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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.

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SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype–Phenotype Association and Precision Diagnosis for Niemann–Pick Disease Types A and B

Wang

Qin

Huang

et al. 2022

Preprint

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Background: Types A and B of the rare genetic disease Niemann–Pick disease (NPD) are caused by mutations in the SMPD1 gene, which encodes sphingomyelin phosphodiesterase (ASM). Except for the liver and spleen enlargement and lung disease, the two subtypes have different onset times, survival times, ASM activities, and neurological abnormalities. To comprehensively explore the genotype-phenotype association and pathophysiological characteristics of NPD, 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, p.Arg3AlafsX76 mutation is highly prevalent in the Chinese population, and 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 in 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. Conclusions: Our study is the first one 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.

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Novel mutations in the SMPD1 gene in Jordanian children with Acid sphingomyelinase deficiency (Niemann-Pick types A and B)

Cited by 5 publications

References 33 publications

SMPD1 gene variants in patients with β-Thalassemia major

SMPD1 gene variants in patients with β-Thalassemia major

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

SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype–Phenotype Association and Precision Diagnosis for Niemann–Pick Disease Types A and B

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