Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population

Hum Mutat. 2001 May;17(5):397-402. doi: 10.1002/humu.1115.

Abstract

The gene MCOLN1 is mutated in Mucolipidosis type IV (MLIV), a neurodegenerative, recessive, lysosomal storage disorder. The disease is found in relatively high frequency among Ashkenazi Jews due to two founder mutations that comprise 95% of the MLIV alleles in this population [Bargal et al., 2000]. In this report we complete the mutation analysis of Jewish and non-Jewish MLIV patients whose DNA were available to us. Four novel mutations were identified in the MCOLN1 gene of severely affected patients: two missense, T232P and F465L; a nonsense, R322X; and an 11-bp insertion in exon 12. The nonsense mutation (R322X) was identified in two unrelated patients with different haplotypes in the MCOLN1 chromosomal region, indicating a mutation hotspot in this CpG site. An in-frame deletion (F408del) was identified in a patient with unusual mild psychomotor retardation. The frequency of MLIV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the two founder mutations. This analysis indicated a heterozygotes frequency of about 1/100. A preferred nucleotide numbering system for MCOLN1 mutations is presented and the issue of a screening program for the detection of high-risk families in the Jewish Ashkenazi population is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Codon, Nonsense / genetics
  • CpG Islands / genetics
  • DNA Mutational Analysis
  • DNA Primers / genetics
  • Exons / genetics
  • Founder Effect
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Haplotypes / genetics
  • Heterozygote
  • Humans
  • Jews / genetics*
  • Membrane Proteins / genetics*
  • Molecular Sequence Data
  • Mucolipidoses / classification
  • Mucolipidoses / epidemiology*
  • Mucolipidoses / genetics*
  • Mutagenesis, Insertional / genetics
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Polymerase Chain Reaction
  • TRPM Cation Channels
  • Transient Receptor Potential Channels
  • White People / genetics*

Substances

  • Codon, Nonsense
  • DNA Primers
  • MCOLN1 protein, human
  • Membrane Proteins
  • TRPM Cation Channels
  • Transient Receptor Potential Channels

Associated data

  • GENBANK/AF249319
  • GENBANK/AF287270