title: Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide.
abstract: An analysis of mutations was performed in 141 Duchenne muscular dystrophy (DMD) patients previously found to be negative for large deletions by standard multiplex PCR assays. Comprehensive mutation scanning of all coding exons, adjacent intronic splice regions, and promoter sequences was performed by DOVAM-S, a robotically enhanced, high throughput method that detects essentially all point mutations. Samples negative for point mutations were further analyzed for duplications by multiplex amplifiable probe hybridization (MAPH). Presumptive causative mutations were detected in 90% of the patients (70% protein truncating point mutations, 13% duplications, and 7% deletions not detected by the standard multiplex screening method). A total of 40 of the mutations are putatively novel. Most duplications involve multiple exons with an average and median size of about 160 and 153 kb, respectively. This is the first analysis of the absolute and relative rates of point mutations in the dystrophin gene. Relative to microdeletions (0.68 x 10(-9) per bp per generation), transitions at CpG dinucleotides are enhanced 150-fold while complex indels, the least common mutation type, are less frequent than microdeletions by a factor of five. The frequency of microdeletions and microinsertions at mononucleotide repeats increases exponentially with length. When compared to the well-studied human factor IX gene (F9), the results are similar, with two exceptions: a hotspot of mutation in the dystrophin gene (c.8713C>T/p.R2905X) at a CpG dinucleotide and an altered size distribution of microdeletions. The hotspot reflects a difference in the underlying pattern of mutation, while the altered size distribution of microdeletions reflects certain abundant sequence motifs within the dystrophin coding sequence (relative to factor IX).
authors.affiliation: Department of Molecular Genetics, City of Hope National Medical Center, Duarte, California 91010-3000, USA.
authors.forename: Carolyn H
authors.initials: CH
authors.lastname: Buzin
authors.forename: Jinong
authors.initials: J
authors.lastname: Feng
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: William
authors.initials: W
authors.lastname: Scaringe
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Johan
authors.initials: J
authors.lastname: den Dunnen
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Steve S
authors.initials: SS
authors.lastname: Sommer
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D004252:DNA Mutational Analysis / Q000379:methods; D016189:Dystrophin / Q000235:genetics*; D005164:Factor IX / Q000235:genetics; D005796:Genes; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D017354:Point Mutation; D017384:Sequence Deletion; D020080:Tandem Repeat Sequences
chemical_list: D016189:Dystrophin; D005164:Factor IX