title: CGG-repeat expansion in the DIP2B gene is associated with the fragile site FRA12A on chromosome 12q13.1.
abstract: A high level of cytogenetic expression of the rare folate-sensitive fragile site FRA12A is significantly associated with mental retardation. Here, we identify an elongated polymorphic CGG repeat as the molecular basis of FRA12A. This repeat is in the 5' untranslated region of the gene DIP2B, which encodes a protein with a DMAP1-binding domain, which suggests a role in DNA methylation machinery. DIP2B mRNA levels were halved in two subjects with FRA12A with mental retardation in whom the repeat expansion was methylated. In two individuals without mental retardation but with an expanded and methylated repeat, DIP2B expression was reduced to approximately two-thirds of the values observed in controls. Interestingly, a carrier of an unmethylated CGG-repeat expansion showed increased levels of DIP2B mRNA, which suggests that the repeat elongation increases gene expression, as previously described for the fragile X-associated tremor/ataxia syndrome. These data suggest that deficiency of DIP2B, a brain-expressed gene, may mediate the neurocognitive problems associated with FRA12A.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Winnepenninckx
authors.forename: Kim
authors.initials: K
authors.lastname: Debacker
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramsay
authors.forename: Dominique
authors.initials: D
authors.lastname: Smeets
authors.forename: Arie
authors.initials: A
authors.lastname: Smits
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.forename: R Frank
authors.initials: RF
authors.lastname: Kooy
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D043283:Chromosome Fragile Sites; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D016013:Likelihood Functions; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
chemical_list: C517831:DIP2B protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger