title: Differences in methylation patterns in the methylation boundary region of IDS gene in Hunter syndrome patients: implications for CpG hot spot mutations.
abstract: Hunter syndrome, an X-linked disorder, results from deficiency of iduronate-2-sulfatase (IDS). Around 40% of independent point mutations at IDS were found at CpG sites as transitional events. The 15 CpG sites in the coding sequences of exons 1 and 2, which are normally hypomethylated, account for very few of transitional mutations. By contrast, the CpG sites in the coding sequences of exon 3, though also normally hypomethylated, account for much higher fraction of transitional mutations. To better understand relationship between methylation status and CpG transitional mutations in this region, the methylation patterns of 11 Hunter patients with transitional mutations at CpG sites were investigated using bisulfite genomic sequencing. The patient cohort mutation spectrum is composed of one mutation in exon 1 (one patient) and three different mutations in exon 3 (10 patients). We confirmed that in normal males, cytosines at the CpG sites from the promoter region to a portion of intron 3 were hypomethylated. However, specific CpG sites in this area were more highly methylated in patients. The patients with p.R8X (exon 1), p.P86L (exon 3), and p.R88H (exon 3) mutations had a hypermethylated condition in exon 2 to intron 3 but retained hypomethylation in exon 1. The same trend was found in four patients with p.A85T (exon 3), although the degree of hypermethylation was less. These findings suggest methylation patterns in the beginning of IDS genomic region are polymorphic in humans and that hypermethylation in this region in some individuals predisposes them to CpG mutations resulting in Hunter syndrome.
authors.affiliation: Department of Pediatrics, Saint Louis University, Pediatric Research Institute, St Louis, MO 63110-2586, USA. tomatsus@slu.edu
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sukegawa
authors.forename: Georgeta G
authors.initials: GG
authors.lastname: Trandafirescu
authors.forename: Monica A
authors.initials: MA
authors.lastname: Gutierrez
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nishioka
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Tadao
authors.initials: T
authors.lastname: Orii
authors.forename: Roseline
authors.initials: R
authors.lastname: Froissart
authors.forename: Irene
authors.initials: I
authors.lastname: Maire
authors.forename: Amparo
authors.initials: A
authors.lastname: Chabas
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.forename: Paola
authors.initials: P
authors.lastname: Di Natale
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Akihiko
authors.initials: A
authors.lastname: Noguchi
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005091:Exons / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016532:Mucopolysaccharidosis II / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D006023:Glycoproteins; C018322:IDS protein, human