Mutations in DDHD2, Encoding an Intracellular Phospholipase A1, Cause a Recessive Form of Complex Hereditary Spastic Paraplegia Janneke H.M. Schuurs-Hoeijmakers,

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Mutations in DDHD2, Encoding an Intracellular Phospholipase A1, Cause a Recessive Form of Complex Hereditary Spastic Paraplegia Janneke H.M. Schuurs-Hoeijmakers,

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Mutations in DDHD2, Encoding an Intracellular Phospholipase A1, Cause a Recessive Form of Complex Hereditary Spastic Paraplegia Janneke H.M. Schuurs-Hoeijmakers, Michael T. Geraghty, Erik-Jan Kamsteeg, Salma Ben-Salem, Susanne T. de Bot, Bonnie Nijhof, Ilse I.G.M. van de Vondervoort, Marinette van der Graaf, Anna Castells Nobau, Irene Otte-Höller, Sascha Vermeer, Amanda C. Smith, Peter Humphreys, Jeremy Schwartzentruber, Bassam R. Ali, Saeed A. Al-Yahyaee, Said Tariq, Thachillath Pramathan, Riad Bayoumi, Hubertus P.H. Kremer, Bart P. van de Warrenburg, Willem M.R. van den Akker, Christian Gilissen, Joris A. Veltman, Irene M. Janssen, Anneke T. Vulto-van Silfhout, Saskia van der Velde-Visser, Dirk J. Lefeber, Adinda Diekstra, Corrie E. Erasmus, Michèl A. Willemsen, Lisenka E.L.M. Vissers, Martin Lammens, Hans van Bokhoven, Han G. Brunner, Ron A. Wevers, Annette Schenck, Lihadh Al-Gazali, Bert B.A. de Vries, Arjan P.M. de Brouwer The American Journal of Human Genetics Volume 91, Issue 6, Pages 1073-1081 (December 2012) DOI: 10.1016/j.ajhg.2012.10.017 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Families 1–4, Photographs of the Face, and Chromatograms Showing Sanger Confirmation of the DDHD2 Mutations Arrows indicate the individuals on whom exome sequencing was performed. The following abbreviations are used: M, mutant allele; −, wild-type allele; and C, control. (A) Family 1 (family identifier: W10-1338) has an affected sister and brother and compound heterozygous frameshift mutations c.1804_1805insT (p.Thr602Ilefs∗18) and c.2057delA (p.Glu686Glyfs∗35). (B) Family 2 has an affected sister and brother and compound heterozygous frameshift and missense mutations c.1386dupC (p.Ile463Hisfs∗6) and c.1978G>C (p.Asp660His). (C) Consanguineous family 3 has seven affected individuals and homozygous mutation c.1546C>T (p.Arg516∗). Pedigree numbering is according to the original pedigree by Al-Yahyaee et al.8 (D) Consanguineous family 4 (family identifier: W12-0041) has one affected male individual and homozygous mutation c.859C>T (p.Arg287∗). (E) The protein structure of DDHD2 includes its four domains (WWE, lipase, SAM, and DDHD), and the position of all identified mutations are indicated. The American Journal of Human Genetics 2012 91, 1073-1081DOI: (10.1016/j.ajhg.2012.10.017) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 CNS Imaging of Individual II-2 of Family 1 (A) Midsagittal T1-weighted MRI of the brain shows a marked thin corpus callosum (arrow). (B) Transverse T2-weighted MRI of the brain shows subtle white-matter hyperintensities (arrows). (C) Proton MRS obtained at a magnetic field of 1.5 tesla. Voxel was fixed just cranial of the basal-ganglia and thalamus area, of which proton MRS at long echo time (144 ms) was obtained. It shows the prominent pathologic lipid peak at 1.3 ppm (arrow), apart from the common spectral peaks of choline (Cho), creatine (Cr), and N-acetylaspartate (NAA). (D) Sagittal T2-weighted MRI of the spine shows a spinal syrinx (arrow). Similar brain abnormalities and proton MRS were found in the other families (Figures S3–S7). The American Journal of Human Genetics 2012 91, 1073-1081DOI: (10.1016/j.ajhg.2012.10.017) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Synapse Morphology and Organization at the Drosophila NMJ of Control and Ddhd-Knockdown Flies Three different RNAi lines, vdrcGD35956, vdrcGD35957, and vdrcKK108121, from the Vienna Drosophila Research Center, were used and compared to their genetic background lines, vdrcGD60000 (for vdrcGD35956 and vdrcGD35957) and vdrcKK60100 (for vdrcKK108121). RNAi was induced with the pan-neuronal UAS-dicer2; elav-Gal4 driver. Drosophila muscle 4 type 1b NMJs were analyzed as previously described.30 (A) Anti-dlg1 (upper panel) and anti-brp immunolabeling (middle panel) at the NMJ of control (vdrcGD60000) and Ddhd-knockdown (vdrcGD35956) larvae, as well as output of computer-assisted analysis with an in house-developed macro (bottom panel). Each white dot represents one active zone. (B) Quantification of active zones shows a significant reduction in all three RNAi lines compared to their genetic-background controls. The p values are from two-sided t tests. Error bars indicate the SEM. The following abbreviation is used: n, number of quantified synaptic terminals. The American Journal of Human Genetics 2012 91, 1073-1081DOI: (10.1016/j.ajhg.2012.10.017) Copyright © 2012 The American Society of Human Genetics Terms and Conditions