RAI1 – Smith-Magenis Syndrome

Smith-Magenis syndrome (MONDO:0008434) is a multisystem congenital disorder characterized by craniofacial anomalies, intellectual disability, sleep disturbance, self-injurious behaviors, and short stature. Most cases arise from a ~3.7 Mb deletion of chromosome 17p11.2 encompassing RAI1 (RAI1), while 10–15% are due to heterozygous point mutations in RAI1 itself. RAI1 encodes a dosage-sensitive transcriptional regulator with key roles in neurodevelopment, circadian rhythm, and growth signaling.

Multiple independent cohorts and mutation screens provide definitive evidence linking RAI1 haploinsufficiency to SMS. In a genotype-phenotype analysis of 31 SMS patients, 10 individuals without 17p11.2 deletions harbored heterozygous RAI1 mutations, and phenotypic comparison showed that RAI1 loss accounts for the majority of SMS features (31 patients; PMID:16845274). Earlier studies identified dominant frameshift mutations in RAI1 in three non-deletion SMS cases (PMID:12652298), and two novel truncating alleles were reported in additional cohorts (PMID:15565467).

RAI1-related SMS follows an autosomal dominant inheritance pattern with most variants arising de novo. Over 10 unrelated probands with RAI1 point mutations have been described (e.g., mother–daughter transmission in two affected individuals; PMID:27683195). Variant spectrum includes nonsense, frameshift, and missense alleles. One representative pathogenic allele is c.5536C>T (p.Gln1846Ter), which truncates the C-terminal transactivation domain and abolishes transcriptional activity.

The mutation spectrum features a hotspot in a heptameric C-tract (c.3103del) leading to recurrent frameshifts; missense variants cluster in the PHD zinc-finger and nuclear localization regions. Truncating mutations uniformly result in loss of nuclear localization, whereas C-terminal missense alleles retain nuclear entry but lose enhancer activation capacity.

Functional studies corroborate the haploinsufficiency mechanism. Rai1-transgenic mice with graded copy-number increases exhibit dosage-dependent growth retardation, hyperactivity, gait abnormalities, and anxiety-related behaviors, modeling human dup(17)(p11.2) and SMS phenotypes (PMID:18285828). In vitro assays of patient-derived RAI1 truncations demonstrate cytoplasmic mislocalization and loss of BDNF-enhancer driven transcriptional activation (PMID:20738874).

Integration of genetic and experimental data supports a definitive gene-disease association. RAI1 haploinsufficiency explains the core SMS phenotype, while deletion of flanking genes modulates cardiac, growth, and hearing anomalies. Diagnostic testing for RAI1 variants is clinically warranted in patients meeting SMS criteria, and functional assays aid variant interpretation. Key take-home: RAI1 point mutations and deletions are a definitive cause of Smith-Magenis syndrome, guiding molecular diagnosis and management.

References

• Nature genetics | 2003 | Mutations in RAI1 associated with Smith-Magenis syndrome PMID:12652298
• Human genetics | 2004 | Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome PMID:15565467
• Genetics in medicine | 2006 | Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum PMID:16845274
• European journal of human genetics | 2008 | How much is too much? Phenotypic consequences of Rai1 overexpression in mice PMID:18285828
• BMC molecular biology | 2010 | Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome PMID:20738874
• American journal of medical genetics. Part A | 2017 | First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation PMID:27683195

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