Ziv Gan-Or, Naima Bouslam, Nazha Birouk, Alexandra Lissouba, Daniel B

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Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia Ziv Gan-Or, Naima Bouslam, Nazha Birouk, Alexandra Lissouba, Daniel B. Chambers, Julie Vérièpe, Alaura Androschuk, Sandra B. Laurent, Daniel Rochefort, Dan Spiegelman, Alexandre Dionne-Laporte, Anna Szuto, Meijiang Liao, Denise A. Figlewicz, Ahmed Bouhouche, Ali Benomar, Mohamed Yahyaoui, Reda Ouazzani, Grace Yoon, Nicolas Dupré, Oksana Suchowersky, Francois V. Bolduc, J. Alex Parker, Patrick A. Dion, Pierre Drapeau, Guy A. Rouleau, Bouchra Ouled Amar Bencheikh The American Journal of Human Genetics Volume 98, Issue 5, Pages 1038-1046 (May 2016) DOI: 10.1016/j.ajhg.2016.04.002 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Mutations Detected in Three Families Affected by CAPN1-Associated HSP The three affected individuals from family A were homozygous for the c.884G>C (p.Arg295Pro) mutation, and all unaffected individuals with available DNA (IV-2, IV-3, V3, and V6) were heterozygous carriers of the mutation. In family B, all four affected individuals with available DNA (IV-1, IV-2, IV-5, and IV-9) were homozygous for the c.1579C>T stop variant (p.Gln527∗), and all unaffected individuals with available DNA (III-2, III-3, and IV-11) were heterozygous carriers of the mutation. In family C, the two affected individuals were compound heterozygous for the frameshift c.406delC (p.Pro136Argfs∗40) mutation and the splicing c.1605+5G>A mutation. Four more unaffected individuals were sequenced: III-1 (father of the affected individuals), III-2 (mother), IV-9 (sister), and IV-15 (brother). III-1 was heterozygous for the c.1605+5G>A mutation and a non-carrier of the frameshift mutation, and III-2 was heterozygous for the c.406delC mutation and a non-carrier of the splicing mutation. IV-9 was a non-carrier of both mutations, and IV-15 was a carrier of the c.1605+5G>A mutation and a non-carrier of the frameshift mutation. The American Journal of Human Genetics 2016 98, 1038-1046DOI: (10.1016/j.ajhg.2016.04.002) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Characteristics and Predictions of the CAPN1 Mutations (A) Structure of CAPN1 and the locations of the four mutations identified in the current study. (B) Functional predictions of all four mutations. (C) Conservation of Arg295 in different species. With a GERP++ score > 2, this amino acid is highly conserved. (D) Three-dimensional model of calpain 1 and the location of the p.Arg295Pro substitution at the end of a β strand and just before the active site at p.Asn296 (PDB: 1ZCM). (E) cDNA produced from lymphoblasts of an affected individual and two control individuals, around exon 14. In the left lane, two cDNA products were observed, suggesting that the c.1605+5G>A mutation affected splicing. (F) Sequencing of cDNA from RT-PCR of the RNA around splicing mutation c.1605+5G>A demonstrated that this mutation caused the skipping of exon 14. (G) Effects of the frameshift mutation c.406delC (p.Pro136Argfs∗40) (top) and the splicing mutation c.1605+5G>A (bottom) on calpain 1. The American Journal of Human Genetics 2016 98, 1038-1046DOI: (10.1016/j.ajhg.2016.04.002) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Branchiomotor Neurons of capn1a-Mo-Injected Embryos Display Abnormal Migration Abnormal development and migration of both nV (trigeminal) and nVII (facial) branchiomotor neurons in 2 dpf Islet1:GFP embryos either not injected or injected with the mismatch Mo (MisMo) or capn1a Mo. Arrows indicate abnormally located cell bodies. R stands for “rhombomere.” The scale bar represents 50 μm. The American Journal of Human Genetics 2016 98, 1038-1046DOI: (10.1016/j.ajhg.2016.04.002) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 Disorganization of the Microtubule Network in the Brain of capn1a Morphants (A and B) Dorsal view of Z-projections of acetylated-tubulin staining in the brain of embryos injected with MisMo (A) and capn1a Mo (B). (C and D) Lateral view of Z-projections of acetylated-tubulin staining in the brain of embryos injected with MisMo (C) and capn1a Mo (D). The dorsal side is toward the top of the image. (E and F) Spinal cord, along the six to eight somites spanning the anus of the embryos, of embryos injected with MisMo (E) and capn1a Mo (F). The dorsal side is toward the top of the image. Double arrows point toward thinner and disorganized motor neuron axons of the capn1a morphants. Solid white arrows show the clusters of tubulin. Asterisks show the fainter staining of the optic tectum of capn1a morphants. In all images, caudal is to the left. The scale bar represents 60 μm. Abbreviations are as follows: ot, optic tectum; tg, trigeminal ganglion; h, hindbrain; c, cerebellum; m, midbrain; tel, telencephalon; ob, olfactory bulb; and sc, spinal cord. The American Journal of Human Genetics 2016 98, 1038-1046DOI: (10.1016/j.ajhg.2016.04.002) Copyright © 2016 American Society of Human Genetics Terms and Conditions