Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders.
Given the phenotypic overlap between SMS and the SMS-like cases, these data may provide some insight into the function of RAI1, including the pathways in which it may be involved and the genes it may regulate.
Validation using real-time quantitative reverse transcriptase polymerase chain reaction confirmed the gene expression profile of 75% of the selected genes analyzed in both HEK293T RAI1 knockdown cells and SMS lymphoblastoid cell lines.
Mouse models with targeted disruption of Rai1 have recapitulated overt SMS phenotypes, including craniofacial abnormalities, obesity, and neurobehavioral anomalies.
Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.
Previous analyses in a mixed genetic background of several SMS mouse models--including Df(11)17/+ and Df(11)17-1/+, which have 2-Mb and 590-kb deletions, respectively, and Rai1(-/+)--revealed that the penetrance of the craniofacial phenotype appears to be influenced by deletion size and genetic background.
To determine the contribution of RAI1 in the neurobehavioral traits in SMS, we performed a battery of behavioral tests on Rai1 mutant mice and the Df(11)17-1/+ mice that have a small deletion of approximately 590 kb.
Although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome.
Obesity and craniofacial abnormalities, which have been reported in SMS mouse models containing a heterozygous deletion of the syntenic SMS critical region, were observed in Rai1(+/-) mice.
RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spectrum of the phenotype remains unclear.