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

Am J Hum Genet
Authors
Keywords
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.

Year of Publication
2014
Journal
Am J Hum Genet
Volume
95
Issue
6
Pages
721-8
Date Published
2014 Dec 04
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2014.10.016
PubMed ID
25480035
PubMed Central ID
PMC4259997
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30NS047101 / NS / NINDS NIH HHS / United States
R01NS048453 / NS / NINDS NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
MOP-102758 / Canadian Institutes of Health Research / Canada
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
Howard Hughes Medical Institute / United States
P01HD070494 / HD / NICHD NIH HHS / United States
R01NS041537 / NS / NINDS NIH HHS / United States
R01NS052455 / NS / NINDS NIH HHS / United States