Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome

Abstract

Smith-Magenis syndrome (SMS) is a mental retardation/multiple congenital anomalies disorder associated with a heterozygous approximately 4-Mb deletion in 17p11.2. Patients with SMS show variability in clinical phenotype despite a common deletion found in>75-80% of patients. Recently, point mutations in the retinoic acid induced 1 (RAI1) gene, which lies within the SMS critical interval, were identified in three patients with many SMS features in whom no deletion was detected. It is not clear if the entire SMS phenotype can be accounted for by RAI1 haploinsufficiency, nor has the precise function of RAI1 been delineated. We report two novel RAI1 mutations, one frameshift and one nonsense allele, in nondeletion SMS patients. Comparisons of the clinical features in these two patients, three of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggest that the majority of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among the individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologues revealed a zinc finger-like plant homeo domain (PHD) at the carboxyl terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex whose function may be altered in individuals with SMS.

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

“…An atypical de novo deletion in one patient caused a loss of the noncoding exon 2, but not of the coding exons. Interestingly, the deleted region is relatively rich in CpG islands 11 and thus an impact on transcription regulation of the RAI1 gene is speculated. Unfortunately, analyses to examine the RAI1 gene transcript were not possible because cultured cells from the patient were not available.…”

“…There are currently 15 reported mutations that have been described in the RAI1 gene. [10][11][12][13][14] We have identified two additional nonsynonymous variants (p.R1217Q, p.Q1389R). The alterations are not located in RAI1 functional domains, but the substituted amino acids have different physical characteristics.…”

“…3,8,9 Mutations in the RAI1 gene have been observed in B10% of all reported SMS patients. [10][11][12][13][14] To date, little is known about the function of human RAI1. RAI1 appears to be a nuclear protein and exhibits transcription factor activity.…”

Advances in Autism Research – The Genomic Basis of ASD

“…SMS results from a de novo, recurrent, 3.7 Mb deletion in 17p11.2 -del(17)(p11.2p11.2) in ~73% of cases, that is a consequence of NAHR mediated by LCRs flanking the region [77][78][79]. However, many of the pleiotropic features of SMS appear to result from haploinsufficiency of a single gene lying in the middle of the SMS critical region, retinoic acid induced 1 (RAI1), as determined by the identification of non-deletion SMS patients with heterozygous point mutations in RAI1 [80][81][82]. Patients with mutations in RAI1 manifest most of the phenotypes observed in subjects with a chromosomal SMS deletion, demonstrating that the reduced dosage of the RAI1 gene alone may cause much of the SMS phenotype [81,83].…”

“…Spanning over 120 kb, the RAI1 gene consists of six exons, of which the third is the largest, containing >90% of the coding region [80,85,96]. All of the point mutations identified in SMS patients to date lie within this exon.…”