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Biallelic Truncating Mutations in FMN2, Encoding the Actin-Regulatory Protein Formin 2, Cause Nonsyndromic Autosomal-Recessive Intellectual Disability
- Source :
- The American Journal of Human Genetics. 95:721-728
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
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.
- Subjects :
- Adult
Male
Dendritic spine
Adolescent
Genetic Linkage
Molecular Sequence Data
Formins
Chromosome Disorders
Genes, Recessive
Biology
Germline
Cohort Studies
Consanguinity
Report
Intellectual Disability
Genetics
Humans
Exome
Pakistan
Genetics(clinical)
Nuclear protein
Induced pluripotent stem cell
Genetics (clinical)
Actin
Sequence Deletion
Base Sequence
Homozygote
Microfilament Proteins
High-Throughput Nucleotide Sequencing
Nuclear Proteins
Sequence Analysis, DNA
Disease gene identification
Actin cytoskeleton
Pedigree
biology.protein
Egypt
Female
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 95
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....02500387b0effdd24d2dc27249d3a2a0