Article Text

Download PDFPDF

Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts
  1. TOSHIYUKI YAMAMOTO*,
  2. HARUAKI NINOMIYA,
  3. MICHIKA MATSUMOTO,
  4. YASUTOSHI OHTA*,
  5. EIJI NANBA*,
  6. YUKIE TSUTSUMI,
  7. KAZUHIRO YAMAKAWA,
  8. GILLES MILLAT§,
  9. MARIE T VANIER§,
  10. PETER G PENTCHEV,
  11. KOUSAKU OHNO
  1. *Gene Research Center, Tottori University, 86 Nishi-machi, Yonago 683-8503, Japan
  2. †Department of Neurobiology, School of Life Sciences, Faculty of Medicine, Tottori University, 86 Nishi-machi, Yonago 683-8503, Japan
  3. ‡Laboratory for Neurogenetics, Brain Science Institute, RIKEN, Wako 351-0198, Japan
  4. §INSERM Unit 189, Lyon-Sud Medical School, and Fondation Gillet-Merieux, Lyon-Sud Hospital, 69921 Oullins, France
  5. ¶National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
  1. Dr Yamamoto,tyamamot{at}grape.med.tottori-u.ac.jp

Statistics from Altmetric.com

Editor—Niemann-Pick disease type C (NP-C, MIM 257220) is a fatal autosomal recessive disorder characterised by progressive neurological deterioration and hepatosplenomegaly. NP-C patients can be classified into four major groups according to the onset of neurological symptoms, that is, early infantile, late infantile, juvenile, and adult forms, and the earlier the clinical onset the more quickly progressive are the symptoms and the shorter is the life span.1-4Complementation analysis using cultured skin fibroblasts indicated the presence of at least two subgroups of NP-C, NPC1 (the major subgroup that comprises >90% of NP-C patients) and NPC2 (the minor subgroup).2-4 In 1997, the NPC1 gene (NPC1) (accession No AF002020) that is responsible for the NPC1 subgroup was identified by positional cloning.5 6 The number ofNPC1 mutations known to date is not far off 100,7-11 taking into account the accumulated data from seven groups presented in a recent international workshop (International Workshop, The Niemann-Pick C Lesion and the Role of Intracellular Lipid Sorting in Human Disease, Bethesda, USA, October 1999).

Because the genomic structure of NPC1 was unknown, initial mutation screening was performed on RT-PCR products or partial genomic amplicons. In our previous study using RT-PCR products, we identified 14 different mutations in 19 alleles from 11 patients, and failed to detect mutations in the remaining three alleles.8 Mutation screening using RT-PCR products has several drawbacks compared with screening using genomic amplicons. For example, mutations that reduce the mRNA stability may escape the screening.12 13 To refine the screening method, we screened a CITB human BAC library (Research Genetics, Huntsville, AL) and isolated a clone 386K10 that contained all the 25 exons ofNPC1 and a 2 kb fragment of 5′UTR. Our analysis using 386K10 confirmed the exon/intron boundary sequences reported by Morriset al …

View Full Text

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.