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. 2014 Sep;166C(3):315-26.
doi: 10.1002/ajmg.c.31413. Epub 2014 Aug 28.

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

Geert Vandeweyer, Céline Helsmoortel, Anke Van Dijck, Anneke T Vulto-van Silfhout, Bradley P Coe, Raphael Bernier, Jennifer Gerdts, Liesbeth Rooms, Jenneke van den Ende, Madhura Bakshi, Meredith Wilson, Ann Nordgren, Laura G Hendon, Omar A Abdulrahman, Corrado Romano, Bert B A de Vries, Tjitske Kleefstra, Evan E Eichler, Nathalie Van der Aa, R Frank Kooy

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

Geert Vandeweyer et al. Am J Med Genet C Semin Med Genet. 2014 Sep.

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.

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Figures

Figure 1
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
Figure 2
a: Schematic representation of the ADNP protein. Symbols: formula image previous cases, formula image new case, formula image controls and formula image cases for which expression analysis was performed. b: Amino acid positions of the different domains.
Figure 3
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
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].
See this image and copyright information in PMC

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