Biallelic Truncating Mutations in FMN2, Encoding the Actin-Regulatory Protein Formin 2, Cause Nonsyndromic Autosomal-Recessive Intellectual Disability

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Biallelic Truncating Mutations in FMN2, Encoding the Actin-Regulatory Protein Formin 2, Cause Nonsyndromic Autosomal-Recessive Intellectual Disability Rosalind Law, Tracy Dixon-Salazar, Julie Jerber, Na Cai, Ansar A. Abbasi, Maha S. Zaki, Kirti Mittal, Stacey B. Gabriel, Muhammad Arshad Rafiq, Valeed Khan, Maria Nguyen, Ghazanfar Ali, Brett Copeland, Eric Scott, Nasim Vasli, Anna Mikhailov, Muhammad Nasim Khan, Danielle M. Andrade, Muhammad Ayaz, Muhammad Ansar, Muhammad Ayub, John B. Vincent, Joseph G. Gleeson The American Journal of Human Genetics Volume 95, Issue 6, Pages 721-728 (December 2014) DOI: 10.1016/j.ajhg.2014.10.016 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 ARID-628 and ARID-49 with Homozygous Inactivating Mutations in FMN2 (A and D) Consanguineous parents and multiple affected individuals suggest recessive inheritance. (B and E) Homozygous exome haplotypes containing FMN2 in telomeric chromosome 1 (arrows). (C and F) ARID-628 homozygous chr1:240,256,799insG (arrow) and ARID-49 showing major-allele control TTCAAACGA, minor-allele control (MA) TTCAAACCA, and diseased TTCAACGA (arrow) chr1:240,370,627delA. (G) Genomic organization and location of mutations for chr1q43–44, including FMN2, from the UCSC Genome Browser; mutations are not predicted to interfere with shorter transcripts. (H) FMN2 encodes a 1,726 residue protein with DEP, FH1, and FH2 domains, several putative sites of phosphorylation (small vertical ticks), and an FMN2-SPIRE1-interacting domain (FSI). (I) RT-PCR of FMN2 primary fibroblasts shows that products are absent in IV-4 but present in the control (C), III-2, and GAPDH fibroblasts, suggesting nonsense-mediated decay. Primer sequencing: FMN2-F, 5′-CCGTCTCAGTCCCCTAATCA-3′; FMN2-R, 5′-ATCCGGGAGCAAAACTTCTC-3′; GAPDH-F, 5′-ATCCCATCACCATCTTCCAG-3′; and GAPDH-R, 5′-CCATCACGCCACAGTTTCC-3′. (J) An immunoblot of FMN2 in primary fibroblasts shows an absence of protein in IV-4 but presence in the control, III-2. GAPDH was used as a loading control. Antibodies: FMN2, Sigma HPA004937, 1:1,000; and GAPDH, Millipore mab374, 1:5,000. The American Journal of Human Genetics 2014 95, 721-728DOI: (10.1016/j.ajhg.2014.10.016) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 FMN2 Is Required for Dendritic-Spine Morphogenesis in Mice (A) P14 hippocampus from Fmn2+/+ and Fmn2−/−. Immunofluorescence showed FMN2 staining in the granule neuron dendritic region (the highlighted section is the CA2 region) of Fmn2+/+ mice but no staining in knockout mice. Phalloidin staining was not overtly different between genotypes. The scale bar represents 150 μm. (B) FMN2 punctae localize along dendrites of cultured murine primary hippocampal neurons at 21 days in vitro. Staining was adjacent to both post- (PSD-95) and pre-synaptic (VGLUT1 and SYNAPSIN) markers but did not fully colocalize. The scale bar represents 5 μm. FMN2: Sigma HPA004937, 1:200. PSD95 Thermo MA1-045, VGLUT1 Synaptic Systems, Inc. #135302, SYNAPSIN Cell Signaling #5297. (C and D) Golgi-stained images of Fmn2+/+ and Fmn2−/− are shown at low and high magnification (FDneurotech Rapid Golgi Stain method). Neuronal morphology was indistinguishable, but spine density was reduced in knockout neurons when Sholl’s method for dendritic arborization was used. The scale bars in (D) and (E) represent 50 μm; in (D′) and (E′) it represents 20 μm. (E) Quantification of spine density per micron of dendrite of hippocampal granule neuron from the CA2 region from three mice of each genotype, two sections per animal, >1,000 spines per animal. ∗p < 0.001 by Student’s t test. The error bar shows SEM (0.80 ± 0.05 versus 0.54 ± 0.04 spines/μm, n = 3 mice of each genotype). The American Journal of Human Genetics 2014 95, 721-728DOI: (10.1016/j.ajhg.2014.10.016) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Reduced Synaptic Density in Human FMN2 Mutant IPSC-Derived Neural Cells (A) FMN2 mutant cells exhibit reduced density of excitatory synapses as assessed by VGlut1 (green) staining of neural cells (see also Figure S4). F-actin was visualized via phalloidin staining (red). (B) Quantification of excitatory synapses per square micron showed reduced density in cells from affected members specifically under the Imaris MeasurementPro module. ∗p < 0.01 by Student’s t test. The error bar represents SEM (0.83 ± 0.085 versus 0.81 ± 0.065 versus 0.47 ± 0.110 in the control individual, unaffected individual, and affected individual, respectively; n = 10 dendrites segmented from each of four neurons from two independent cultures per individual). The American Journal of Human Genetics 2014 95, 721-728DOI: (10.1016/j.ajhg.2014.10.016) Copyright © 2014 The American Society of Human Genetics Terms and Conditions