Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability

Am J Hum Genet. 2014 Dec 4;95(6):721-8. doi: 10.1016/j.ajhg.2014.10.016.

Abstract

Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / physiopathology
  • Cohort Studies
  • Consanguinity
  • Egypt
  • Exome / genetics
  • Female
  • Formins
  • Genes, Recessive
  • Genetic Linkage
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Male
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pakistan
  • Pedigree
  • Sequence Analysis, DNA
  • Sequence Deletion*

Substances

  • Formins
  • Microfilament Proteins
  • Nuclear Proteins
  • formin 2 protein, human

Associated data

  • dbGaP/PHS000288