title: Mosaicism for a full mutation, premutation, and deletion of the CGG repeats results in 22% FMRP and elevated FMR1 mRNA levels in a high-functioning fragile X male.
abstract: The molecular basis in the majority of fragile X patients results from expansion of the CGG repeats in the FMR1 gene causing its transcriptional silencing and deficiency of its encoded protein FMRP. In this communication, we report on a male patient who lacks the characteristic physical features of fragile X and carries a fully methylated mutation, a premutation, a non-methylated full mutation, and a microdeletion encompassing the entire CGG repeat region and 42 bp of upstream flanking sequence. Southern blot analysis revealed that the methylated full mutation accounted for only 10% of his genotype while the premutation/non-methylated full mutation and the microdeletion constituted 37% and 53%, respectively. Immunofluorescent staining of FMRP demonstrated the presence of 22% FMRP in his peripheral blood leukocytes and quantitative RT-PCR revealed a 3.6-fold elevation of FMR1 mRNA levels. Developmental assessments indicated that while he has a learning disability, he does not have mental retardation. Because previous reports had noted that 28% FMRP expression is associated with a characteristic fragile X phenotype, we propose that in our patient the association of 22% FMRP levels with normal physical features and a high-functioning status may have resulted from increased FMRP stability by a mechanism that takes into account the CGG microdeletion and elevated mRNA levels.
authors.affiliation: Department of Laboratory Medicine, University of California-San Francisco, 185 Berry Street, San Francisco, CA 94107, USA.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Han
authors.forename: Berkley R
authors.initials: BR
authors.lastname: Powell
authors.forename: Judith L
authors.initials: JL
authors.lastname: Phalin
authors.forename: Farid F
authors.initials: FF
authors.lastname: Chehab
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D004247:DNA / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D004247:DNA; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human