title: Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.
abstract: Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York.
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York.
authors.forename: Efrat
authors.initials: E
authors.lastname: Eliyahu
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York.
authors.forename: Nataly
authors.initials: N
authors.lastname: Shtraizent
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: McGovern
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York. Electronic address: edward.schuchman@mssm.edu.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
mesh_terms: D000328:Adult; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D018392:Genomic Imprinting; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D000077209:Decitabine; D013108:Sphingomyelin Phosphodiesterase; D001374:Azacitidine