Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy Rachael M. Duff, Valerie Tay, Peter Hackman, Gianina Ravenscroft,

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Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy Rachael M. Duff, Valerie Tay, Peter Hackman, Gianina Ravenscroft, Catriona McLean, Paul Kennedy, Alina Steinbach, Wiebke Schöffler, Peter F.M. van der Ven, Dieter O. Fürst, Jaeguen Song, Kristina Djinović-Carugo, Sini Penttilä, Olayinka Raheem, Katrina Reardon, Alessandro Malandrini, Simona Gambelli, Marcello Villanova, Kristen J. Nowak, David R. Williams, John E. Landers, Robert H. Brown, Bjarne Udd, Nigel G. Laing The American Journal of Human Genetics Volume 88, Issue 6, Pages 729-740 (June 2011) DOI: 10.1016/j.ajhg.2011.04.021 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Muscle Wasting in Patients of the Victorian and Italian Distal Myopathy Families (A) A computed tomography (CT) scan of the lower leg in a 39-year-old female patient from the Victorian family. Severe fatty degeneration of both soleus muscles and right peroneal muscles is evident; there is slightly less involvement of medial and lateral gastrocnemius muscles and radiologically normal anterior compartment and tibialis posterior muscles. (B) CT imaging of the lower legs in the Italian male patient. Severe fatty degeneration of soleus and gastrocnemii muscles are evident with less severe changes in peroneal muscles and sparing of anterior compartment and tibialis posterior muscles. (C) Marked atrophy of thenar muscles in patient III:3 from the Italian family (marked by arrow). The American Journal of Human Genetics 2011 88, 729-740DOI: (10.1016/j.ajhg.2011.04.021) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigree of the Italian Family Pedigree of the Italian family with distal myopathy identified in this study. The segregation of haplotypes around FLNC chromosome 7 are represented by colored bars. Samples with DNA available for study are marked with an asterisk (∗). Inferred haplotypes are enclosed with brackets. A recombination between microsatellites D7S2519 and D7S2531 was observed in individual III:1. FLNC is located between markers D7S2501 and D7S2519. The American Journal of Human Genetics 2011 88, 729-740DOI: (10.1016/j.ajhg.2011.04.021) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutations in the Filamin C Protein (A) The filamin C protein with the position of the two mutations identified in this report marked on the ABD. The mutations in Ig-like repeats 7 and 24 responsible for myofibrillar myopathy [MIM 609524] are also indicated. (B) Chromatogram showing the c.752T>C heterozygous missense mutation resulting in a p.Met251Thr amino acid change identified in the Victorian family. (C) Chromatogram showing the c.577G>A missense mutation resulting in a p.Ala193Thr amino acid change identified in the Italian family. (D) Multiple sequence alignment of homologous ABDs with known mutations highlighted in red, mutations investigated in transient transfection experiments in cell culture in this report highlighted in green, and the position of the mutations identified in this study highlighted in gray. The American Journal of Human Genetics 2011 88, 729-740DOI: (10.1016/j.ajhg.2011.04.021) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Protein Foldedness and Actin-Binding Assays (A) Circular dichroism spectroscopy in the far UV range was performed with purified, bacterially expressed wild-type and mutant filamin ABD constructs. The mean residue ellipticity (MRE) shows two minima in the spectrum at 208 and 222 nm and a maximum at 200 nm, typical for the presence of a high proportion of α helices. Note that the spectra of the wild-type and p.Ala193Thr mutant are almost identical, whereas the MRE of the p.Met251Thr mutant shows a slightly decreased ellipticity compared to the ellipticity of the p.Ala193Thr and wild-type constructs. (B and C) Actin-binding assays of filamin C wild-type and mutant ABDs. (B) The results of high-speed F-actin cosedimentation assays. The numbers on top of each lane indicate the amount of recombinant ABD added to 5 μM actin. Given are the supernatant (S) and pellet (P) fractions. The following abbreviations are used: C1, control without ABD; C2, control without actin. (C) Binding curves with F-actin. The mutant proteins exhibited increased actin-binding activity, represented by a change in dissociation constant (Kd) to 3.7 μM for p.Met251Thr and 5.7 μM for p.Ala193Thr when compared to the wild-type filamin C (Kd = 8.2 μM). The American Journal of Human Genetics 2011 88, 729-740DOI: (10.1016/j.ajhg.2011.04.021) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 5 Transient Transfection of Full-Length Wild-Type or Mutant Filamin C in PtK2 and C2C12 Cells Shown are immunoflouorescence micrographs of PtK2 (A, B, and C) or C2C12 (D, E, and F) cells transfected with full-length, EGFP-tagged, wild-type (A and D) mutant p.Ala193Thr (B and E) or mutant p.Met251Thr (C and F) filamin C. Note that in both cell types all EGFP fusion proteins are targeted to stress fibers. Only the mutant constructs are additionally localized either in numerous differentially sized aggregates (B, C, and E) or in one or a few large aggregates. (F) Note that primarily the larger aggregates (arrowheads) are costained by F-actin. The scale bar represents 20 μm. The American Journal of Human Genetics 2011 88, 729-740DOI: (10.1016/j.ajhg.2011.04.021) Copyright © 2011 The American Society of Human Genetics Terms and Conditions