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.

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

“…70% of SMS patients have a ~3.7 Mb interstitial deletion of chromosome 17p11.2 that contains 76 genes (Elsea and Girirajan, 2008). Importantly, 10% of SMS patients harbor point mutations or small deletions causing haploinsufficiency of a single gene within this region, Retinoic Acid Induced 1 ( RAI1 ) (Dubourg et al, 2014; Slager et al, 2003). Patients with RAI1 mutations exhibit almost all of the core features of SMS, indicating that RAI1 is the dosage-sensitive gene responsible for most symptoms even in patients with large deletions.…”

Rai1 frees mice from the repression of active wake behaviors by light

“…Because patients with Rai1 mutations display most of the SMS features (Edelman et al, 2007; Potocki et al, 2003), including the sleep/circadian phenotype, Rai1 haplo-insufficiency is thought to be causal (Smith et al, 1998a; Dubourg et al, 2014). A mouse model for SMS has been engineered and Rai1 haplo-insufficient mice recapitulate some of the SMS features such as obesity and craniofacial phenotypes (Bi et al, 2005).…”

First evidence of Smith–Magenis syndrome in mother and daughter due to a novel RAI mutation

“…To date, more than 30 variations in RAI1 have been associated with SMS [Slager et al, ; Dubourg et al, ; HGMD Professional, version December 2015.4]. All described mutations are clustered in exon 3, which encodes more than 95% of the protein.…”