Of interest, the Arg----Leu substitution occurred in one of the ASM alleles from the two Ashkenazi Jewish NPD type B patients studied and in none of the ASM alleles of 15 non-Jewish type B patients.
Of interest, the Arg----Leu substitution occurred in one of the ASM alleles from the two Ashkenazi Jewish NPD type B patients studied and in none of the ASM alleles of 15 non-Jewish type B patients.
To evaluate the feasibility of somatic gene therapy for the treatment of these disorders, retroviral-mediated gene transfer was used to introduce the full-length ASM cDNA into cultured fibroblasts from two unrelated type A NPD patients.
Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients.
Transient expression of the fsL178, L261X, and M382I mutations in COS-1 cells demonstrated that these lesions did not produce catalytically active ASM, consistent with the severe neuronopathic Type A NPD phenotype.
Recently, the full-length cDNA and genomic sequences encoding ASM have been isolated and the nature of the molecular lesions causing NPD has been investigated.
To evaluate the feasibility of somatic gene therapy for the treatment of these disorders, retroviral-mediated gene transfer was used to introduce the full-length ASM cDNA into cultured fibroblasts from two unrelated type A NPD patients.
Transient expression of the fsL178, L261X, and M382I mutations in COS-1 cells demonstrated that these lesions did not produce catalytically active ASM, consistent with the severe neuronopathic Type A NPD phenotype.
Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients.
In addition, novel selection procedures were developed to separate retrovirally corrected and noncorrected NPD fibroblasts based on the receptor-mediated delivery of a fluorescently (pyrene)-labeled sphingomyelin (P12-SPM) to the lysosomes of cells using liposomes coated with apolipoprotein E. In this study, we have used a different, fluorescent derivative of sphingomyelin (lissamine-rhodamine dodecanoyl sphingomyelin; LR12-SPM) to extend and improve this selection system.
Type B NPD cells were transduced with retroviral vectors expressing ASM, labeled with lissamine rhodamine sphingomyelin (LR-SPM), and subjected to preparative fluorescence-activated cell sorting (FACS).
Thus, the ASM deficient mice should be of great value for studying the pathogenesis and treatment of NPD, and for investigations into the role of ASM in signal transduction and apoptosis.
A novel point mutation in the lysosomal acid sphingomyelinase gene has been identified in the recently reported Serbian family with a clinically and biochemically atypical intermediate form of Niemann-Pick disease.
To characterize the mutations causing NPD in Japanese population, we analyzed the genomic sequence of ASM from a Japanese patient with type A NPD by PCR amplification and sequencing.A new mutation, Y446C, was identified.
PCR primers were designed to amplify the repeat region and over 700 normal and NPDASM alleles were analyzed among Ashkenazi Jewish and non-Jewish populations.
A novel single base pair deletion in the acid sphingomyelinase (ASM) gene (677delT in the cDNA) was identified in 12 Israeli Arab families with Niemann-Pick disease (NPD) type A.
Fluorescence-based selection of gene-corrected hematopoietic stem and progenitor cells from acid sphingomyelinase-deficient mice: implications for Niemann-Pick disease gene therapy and the development of improved stem cell gene transfer procedures.
MRI was performed in two siblings with the neuropathic sphingomyelinase deficiency caused by identical mixed heterozygosity in the structural acid sphingomyelinase gene.