Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Desnick, Jonathan P.; Kim, Jungmin; He, Xingxing; Wasserstein, Melissa P.; Simonaro, Calogera M.; Schuchman, Edward H.

doi:10.2119/molmed.2010.00017

Cited by 46 publications

(27 citation statements)

References 10 publications

(13 reference statements)

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“…This mutation in RsASML corresponds to the H427R mutation in human aSMase found in a subset of Niemann-Pick Type A patients [37]. RsASML H280R did not display any activity towards pNPPC (Fig.…”

Section: Resultsmentioning

confidence: 65%

Identification and Biochemical Characterization of an Acid Sphingomyelinase-Like Protein from the Bacterial Plant Pathogen Ralstonia solanacearum that Hydrolyzes ATP to AMP but Not Sphingomyelin to Ceramide

Airola

Tumolo²,

Snider³

et al. 2014

PLoS ONE

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Acid sphingomyelinase (aSMase) is a human enzyme that catalyzes the hydrolysis of sphingomyelin to generate the bioactive lipid ceramide and phosphocholine. ASMase deficiency is the underlying cause of the genetic diseases Niemann-Pick Type A and B and has been implicated in the onset and progression of a number of other human diseases including cancer, depression, liver, and cardiovascular disease. ASMase is the founding member of the aSMase protein superfamily, which is a subset of the metallophosphatase (MPP) superfamily. To date, MPPs that share sequence homology with aSMase, termed aSMase-like proteins, have been annotated and presumed to function as aSMases. However, none of these aSMase-like proteins have been biochemically characterized to verify this. Here we identify RsASML, previously annotated as RSp1609: acid sphingomyelinase-like phosphodiesterase, as the first bacterial aSMase-like protein from the deadly plant pathogen Ralstonia solanacearum based on sequence homology with the catalytic and C-terminal domains of human aSMase. A biochemical characterization of RsASML does not support a role in sphingomyelin hydrolysis but rather finds RsASML capable of acting as an ATP diphosphohydrolase, catalyzing the hydrolysis of ATP and ADP to AMP. In addition, RsASML displays a neutral, not acidic, pH optimum and prefers Ni2+ or Mn2+, not Zn2+, for catalysis. This alters the expectation that all aSMase-like proteins function as acid SMases and expands the substrate possibilities of this protein superfamily to include nucleotides. Overall, we conclude that sequence homology with human aSMase is not sufficient to predict substrate specificity, pH optimum for catalysis, or metal dependence. This may have implications to the biochemically uncharacterized human aSMase paralogs, aSMase-like 3a (aSML3a) and aSML3b, which have been implicated in cancer and kidney disease, respectively, and assumed to function as aSMases.

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Section: Resultsmentioning

confidence: 65%

Identification and Biochemical Characterization of an Acid Sphingomyelinase-Like Protein from the Bacterial Plant Pathogen Ralstonia solanacearum that Hydrolyzes ATP to AMP but Not Sphingomyelin to Ceramide

Airola

Tumolo²,

Snider³

et al. 2014

PLoS ONE

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“…In patient 15, both p.Ser250Arg and p.Glu471Lys mutations were of maternal inheritance. Previously, the p.Ser250Arg mutation has been reported in combination with a premature stop codon, in a Dutch patient with a mild form of type A NPD [10]. In this study, we were unable to determine the pathogenicity of p.Glu471Leu.…”

Section: Resultsmentioning

confidence: 70%

“…Another variation, p.Ala541Thr, was identified on the same allele as p.Pro533Leu, in patient 4. To fully understand the complete effects of these three variations, expression studies need to be conducted as previously reported [10]. …”

Section: Resultsmentioning

confidence: 99%

“…It is very interesting that with the exception of five exon point mutations, c.688C>T (p.Arg230Cys) [7], c.748A>T(p.Ser250Arg) [13], c.759C>A (p.Asp253Glu) [14], c.1565A>G (p.Asn522Ser) [10], c.1492C>T (p.Arg498Cys) [15], and a small insertion, c.1095_1096insG [7], the majority of mutations, including c.4delC, c.147_150del4, c.1307-1312dup6, c.842-849dup8, p.Glu248X, p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Pro533Leu, p.Val559Leu and p.Tyr500His, were novel according the SMPD1 gene mutation database (http://www.hgmd.cf.ac.uk). These newly detected mutations have been deposited in the public databases dbSNP, with the batch accession number 1057561.…”

Section: Resultsmentioning

confidence: 99%

“…Homogenates of leukocytes from patients’ peripheral blood were used to measure ASM activity as previously reported with minor modification [10]. Briefly, leukocytes, isolated from blood cell lysates, were stored at −80°C until analysis.…”

Section: Methodsmentioning

confidence: 99%

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Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease

Zhang

Wang

Gong

et al. 2013

Orphanet Journal of Rare Diseases

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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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SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

et al. 2015

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Niemann-Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease-causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus-specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B.

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Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Cited by 46 publications

References 10 publications

Identification and Biochemical Characterization of an Acid Sphingomyelinase-Like Protein from the Bacterial Plant Pathogen Ralstonia solanacearum that Hydrolyzes ATP to AMP but Not Sphingomyelin to Ceramide

Identification and Biochemical Characterization of an Acid Sphingomyelinase-Like Protein from the Bacterial Plant Pathogen Ralstonia solanacearum that Hydrolyzes ATP to AMP but Not Sphingomyelin to Ceramide

Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

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