Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

Abstract

Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions.

Keywords: 17p11.2; Mutation; RAI1; Smith-Magenis syndrome.

Fig. 1

Photographs of faces and extremities of some patients carrying an RAI1 mutation.

Fig. 2

Diagram showing the structure of RAI1 in the genome with 6 exons and summarizing truncating mutations associated with SMS. All truncating mutations reported to date are indicated, including those described in this study¹ and in Slager et al. [2003]², Bi et al. [2004]³, Girirajan et al. [2005]⁴, Girirajan et al. [2006]⁵, Bi et al. [2006]⁶, Truong et al. [2010]⁷, and Vilboux et al. [2011]⁸: 4 nonsense (indicated by lightning flashes) and 17 frameshift (indicated by arrows) mutations. The numbering of nucleotides is based on GenBank NM_030665.3. The filled boxes represent the RAI1 coding region, and the hollow boxes represent noncoding regions.