Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia Elodie Martin, Rebecca Schüle, Katrien.

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Date of download: 5/30/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Biotin-Responsive Basal Ganglia Disease in Ethnic.

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Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia Elodie Martin, Rebecca Schüle, Katrien Smets, Agnès Rastetter, Amir Boukhris, José L. Loureiro, Michael A. Gonzalez, Emeline Mundwiller, Tine Deconinck, Marc Wessner, Ludmila Jornea, Andrés Caballero Oteyza, Alexandra Durr, Jean-Jacques Martin, Ludger Schöls, Chokri Mhiri, Foudil Lamari, Stephan Züchner, Peter De Jonghe, Edor Kabashi, Alexis Brice, Giovanni Stevanin The American Journal of Human Genetics Volume 92, Issue 2, Pages 238-244 (February 2013) DOI: 10.1016/j.ajhg.2012.11.021 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations in GBA2 (A–D) Family trees and segregation analysis of the mutations identified in individuals of families TUN35 (A), Ng121 (B), F18310 (C), and FSP824 (D). The following symbols are used: squares for males, circles for females; filled symbols for affected individuals; gray symbols for subjects not clinically assessed; double line for consanguinity; m, mutation; +, wild-type; ∗, sampled individuals. Sequencing chromatograms of mutations c.518G>A (p.Trp173∗), c.700C>T (p.Arg234∗), c.1888C>T (p.Arg630Trp), and c.1471_1474dupGGCA (p.Thr492Argfs∗9) are in Figure S1. (E) Graphic representation of the exon organization of GBA2 on chromosome 9 (gray boxes) and the location of the mutations (black arrows). The GBA2 transcript is 3,611 bp long (CDS 2,784 bp) and is composed of 17 exons that encode a 927 amino acid protein. White boxes show the exons encoding the glucosylceramidase domain. The American Journal of Human Genetics 2013 92, 238-244DOI: (10.1016/j.ajhg.2012.11.021) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain Imaging in SPG46-Affected Individuals (A) Sagittal brain magnetic resonance imaging (MRI) in subject FSP824-V.14 after 14 years of disease duration, showing a very slight thinning of the corpus callosum (red arrow). (B and C) Sagittal and transversal flair MRI of individual F18310-V.16484 after 39 years of disease duration. The atrophy of the corpus callosum (B, red arrow) and of the cerebellar (B, blue arrow) and cerebral (B, white arrow) cortex are evident in the absence of relevant white matter disease (C). (D and E) Sagittal T1- and transversal axial T2-weighted MRI images of subject Ng121-II.2 after 65 years of disease duration, showing severe atrophy of her cerebellum (D, blue arrow) and cerebrum (white arrows) with mesencephalon atrophy (D, hummingbird/colibri sign, green arrow) and pronounced white matter lesions (E, black arrowhead). The American Journal of Human Genetics 2013 92, 238-244DOI: (10.1016/j.ajhg.2012.11.021) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 zGba2 Inactivation Induces Morphological Phenotypes and Abnormal Motoneuronal Outgrowth in Zebrafish Larvae (A–D) Whereas 48 hpf embryos injected with 0.1 pmol of the control AMO mmzGba2aug (B) were phenotypically indistinguishable from noninjected controls (A), injection of 0.1 pmol zGba2aug (D) impaired embryonic development of the caudal region, with some morphants showing shortened and/or twisted tails. Most of the injected morphants were normal looking even when they showed abnormal locomotion (C). Magnification ×44. (E) Classification of morphant phenotypes observed after injection of AMOs with or without mRNA. The numbers of noninjected controls and different zGba2 morphants are indicated in parentheses. ∗p < 0.002, ∗∗p < 0.001. (F–I) Noninjected and zGba2 morphants were analyzed for Znp-1 staining in spinal neurons. In contrast to noninjected larvae and to morphants injected with mmzGba2 (F) or zGba2aug + hGBA2 WT mRNA (H), morphants injected with the zGba2aug AMO in presence (I) or absence (G) of the mutated c.1888C>T RNA showed dramatically impaired axonal outgrowth leading to truncated axons (arrowheads). Axon trajectories are disturbed; ectopic and aberrant motor axon branches can be seen (arrows). Scale bar represents 50 μm. The American Journal of Human Genetics 2013 92, 238-244DOI: (10.1016/j.ajhg.2012.11.021) Copyright © 2013 The American Society of Human Genetics Terms and Conditions