title: Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population.
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.
authors.affiliation: Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bargal
authors.forename: N
authors.initials: N
authors.lastname: Avidan
authors.forename: T
authors.initials: T
authors.lastname: Olender
authors.forename: E
authors.initials: E
authors.lastname: Ben Asher
authors.forename: M
authors.initials: M
authors.lastname: Zeigler
authors.forename: A
authors.initials: A
authors.lastname: Raas-Rothschild
authors.forename: A
authors.initials: A
authors.lastname: Frumkin
authors.forename: O
authors.initials: O
authors.lastname: Ben-Yoseph
authors.forename: Y
authors.initials: Y
authors.lastname: Friedlender
authors.forename: D
authors.initials: D
authors.lastname: Lancet
authors.forename: G
authors.initials: G
authors.lastname: Bach
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D018703:Founder Effect; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009081:Mucolipidoses / Q000145:classification / Q000453:epidemiology* / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D016133:Polymerase Chain Reaction; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D044465:White People / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; C416674:MCOLN1 protein, human; D008565:Membrane Proteins; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels