title: RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome.
abstract: Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030-3498, USA. wbi@bcm.tmc.edu
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: G Mustafa
authors.initials: GM
authors.lastname: Saifi
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Xin
authors.initials: X
authors.lastname: Shi
authors.forename: Barbara
authors.initials: B
authors.lastname: Szomju
authors.forename: Helen
authors.initials: H
authors.lastname: Firth
authors.forename: R Ellen
authors.initials: RE
authors.lastname: Magenis
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D020080:Tandem Repeat Sequences; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D018911:Trinucleotide Repeats
chemical_list: C431552:RAI1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA