The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism

Abstract

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. Based on its functional domains, ADNP is a presumed transcription factor. 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. 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. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th 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. 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.

Keywords: ADNP; BAF complexes; SWI/SNF; autism.

Figure 1

http://adnpgene.com forms a portal of a collaborative research project to further characterize the phenotype and future development of patients with ADNP mutations.

Figure 2

a: Schematic representation of the ADNP protein. Symbols: previous cases, new case, controls and cases for which expression analysis was performed. b: Amino acid positions of the different domains.

Figure 3

a–f: Patients 1 (a), 2 (b), 4 (c), 5 (d), 6 (e) and 8 (f) at young ages. Note the clinical similarities, including a prominent forehead, a thin upper lip and a broad nasal bridge. Reproduced with permission from Helsmoortel et al., 2004.

Figure 4

First-level interaction partners of ADNP. Data were retrieved from the STRING database and are based on experimental data only [von Mering et al., 2007].