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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Animals
  • Autistic Disorder / etiology
  • Autistic Disorder / genetics*
  • Child, Preschool
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Face / abnormalities
  • Hand Deformities, Congenital / genetics
  • Haploinsufficiency / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Mice, Knockout
  • Micrognathism / genetics
  • Mutation*
  • Neck / abnormalities
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligopeptides / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ADNP protein, human
  • Adnp protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Oligopeptides
  • SMARCA2 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases
  • davunetide

Supplementary concepts

  • Coffin-Siris syndrome