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In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity.

ABSTRACT: Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.

SUBMITTER: Ancien F

PROVIDER: S-EPMC8123603 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundClinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce.MethodsA cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations.ResultsThe majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele.ConclusionsThe Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder.

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In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity.

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