19417
The Transcriptional Regulator Adnp Links the Nbaf(mSWI/SNF) Complexes with Autism
Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. remodeling complex. Compared to controls, the frequency of truncating mutations in ADNP is significantly higher in patients (p:0.001852, odds ratio 13.24668, one-sided Fisher’s exact test). We estimated this gene to be mutated in approximately 0.2% of ASD cases, making it one of the most frequent ASD genes known to date. Based on its functional domains, ADNP is a presumed transcription factor.
Objectives:
To understand more of the functional and clinical consequences of mutations in ADNP.
Methods:
A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. Functional studies include the expression profiling of the mutated cell lines.
Results:
The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C- terminus to three of its core components. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an additional patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model.
Conclusions:
While we are beginning to understand the genotype-phenotype correlation, it is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.