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Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease

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Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease Cell, Vol. 93, 973±983, June 12, 1998, Copyright 1998 by Cell Press Spastic Paraplegia and OXPHOS Impairment CausedbyMutationsinParaplegin, a Nuclear-Encoded Mitochondrial Metalloprotease Giorgio Casari,1 Maurizio De Fusco,1 Sonia Ciarmatori,1 is a genetically heterogeneous group of neurodegenera- Massimo Zeviani,2 Marina Mora,2 Patricio Fernandez,2,8 tive disorders affecting approximately 1 in 10,000 indi- Giuseppe De Michele,3 Alessandro Filla,3 viduals (Filla et al., 1992; Polo et al., 1993). Patients with Sergio Cocozza,4 Roberto Marconi,5 Alexandre DuÈ rr,6 HSP typically show leg stiffness and gait disturbance, Bertrand Fontaine,6 and Andrea Ballabio1,7,9 decreased perception of sharp stimulation, and dimin- 1 Telethon Institute of Genetics and Medicine (TIGEM) ished vibratory sense in the distal lower limbs. Both the 2 National Neurologic Institute ªC. Bestaº age of onset and severity of the symptoms are highly 20132 Milan variable even among individuals from the same family Italy (Harding, 1981; DuÈ rr et al., 1994). 3 Department of Neurology In addition to the above-described clinical spectrum, 4 Department of Molecular and Cellular Biology which is typical of the ªpureº form of HSP, several pa- Pathology and CEOS-CNR tients have been shown to have ªcomplicatedº forms of Federico II University HSP characterized by the presence of additional neuro- 80136 Naples logical and nonneurological symptoms such as mental Italy retardation, peripheral neuropathy, amyotrophy, ataxia, 5 Department of Neurology retinitis pigmentosa, optic atrophy, deafness, and ich- Misericordia Hospital thyosis (Bonneau et al., 1993; Gigli et al., 1993; Lizcano- 58100 Grosseto Gil et al., 1997; Webb et al., 1997). Albeit some of these Italy forms have been found to segregate in families, it is still 6 Federation de Neurologie and INSERM unclear whether complicated forms of HSP represent Hopital de la Salpetriere distinct genetic entities or variant presentations of pure 75013 Paris HSP. However, even in pure forms of HSP (i.e., with clin- France ical features limited to the lower segments), a broader 7 Universita' Vita Salute subclinical involvement of the nervous system has been San Raffaele Biomedical Science Park demonstrated (Tedeschi et al., 1991; DuÈ rr et al., 1994). 20132 Milan Currently, no specific treatment is available to prevent, Italy cure, or delay progression of symptoms of HSP. 8 Children's Hospital ªBambino GesuÁ º Little is known about the pathogenesis of HSP. Elec- 00165 Rome trophysiologic (Pelosi et al., 1991; Schady et al., 1991) Italy and pathologic (Rhein, 1914; Sutherland, 1975) findings point to the corticospinal tracts, dorsal columns, and, to a lesser extent, the spinocerebellar fibers as the struc- Summary tures primarily affected by HSP. These represent the longest axons of the central nervous system. Interest- Hereditary spastic paraplegia (HSP) is characterized ingly, degeneration occurs only in the distal portion of by progressive weakness and spasticity of the lower these structures, while sparing the neuronal cell bodies limbs due to degeneration of corticospinal axons. We (i.e., pyramidal neurons and sensory neurons of the found that patients from a chromosome 16q24.3± dorsal root ganglia) of degenerating fibers. Peripheral linked HSP family are homozygous for a 9.5 kb dele- nerves are also normal and there are no signs of demye- tion involving a gene encoding a novel protein, named Paraplegin. Two additional Paraplegin mutations, both linization (Fink, 1997; Harding, 1981; Reid, 1997). resulting in a frameshift, were found in a complicated Autosomal dominant, autosomal recessive, and X-linked and in a pure form of HSP. Paraplegin is highly homolo- forms of HSP have been described, indicating genetic gous to the yeast mitochondrial ATPases, AFG3, heterogeneity (Harding, 1981; Fink, 1997; Reid, 1997). RCA1, and YME1, which have both proteolytic and Linkage studies identified three loci for autosomal domi- chaperon-like activities at the inner mitochondrial nant forms, SPG3 (Hazan et al., 1993), SPG4 (Hazan et membrane. Immunofluorescence analysis and import al., 1994), and SPG6 (Fink et al., 1995), on chromosomes experiments showed that Paraplegin localizes to mito- 14q, 2p, and 15q, respectively. One locus, SPG5 (Hentati chondria. Analysis of muscle biopsies from two pa- et al., 1994), involved in autosomal recessive HSP has tients carrying Paraplegin mutations showed typical been mapped to chromosome 8q. The study of families signs of mitochondrial OXPHOS defects, thus sug- in which mapping to any of these loci has been excluded gesting a mechanism for neurodegeneration in HSP- indicates the presence of additional loci for autosomal type disorders. recessive HSP (Hentati et al., 1994). Two distinct forms of HSP, SPG1 and SPG2, have been assigned to the X Introduction chromosome and found to be due to mutations in the L1CAM and PLP genes located on Xq28 (Jouet et al., Progressive weakness and spasticity of the lower limbs 1994) and Xq22 (Saugier-Veber et al., 1994), respec- are the clinical hallmarks of hereditary spastic paraple- tively. With the exception of these two forms, in which gia (HSP) (Harding, 1981; Fink, 1997; Reid, 1997). This spastic paraplegia is part of the clinical spectrum of complex neurological syndromes such as Pelizaeus- 9 To whom correspondence should be addressed. Merzbacher and MASA syndromes, no genes involved Cell 974 Figure 1. Homozygous Deletion Identified in Patients from a Consanguineous Italian Fam- ily with Autosomal Recessive HSP (A) PCR analysis using primers c1-c2 on HSP family 1; DNA from affected individuals failed to amplify. One affected and two healthy members were not available for the analysis and were withdrawn from the pedigree struc- ture. M,100 bp DNA molecular weight marker. (B) Southern blot analysis of a control (C) and patient 10 (pt10) DNA probed with the 1.1 kb insert of EST clone 154386. in HSP have yet been identified. The cloning of HSP genes. One of these genes, CMAR (cell adhesion mole- genes is a critical step in understanding the pathoge- cule regulator; GenBank accession number S54769), netic mechanisms underlying this group of disorders. was originally reported as a 459 bp partially character- Recently, we mapped the locus of a new form of pure ized transcript colinear with genomic DNA and found to autosomal recessive HSP to 16q24.3 (SPG7) (De Michele be involved in the suppression of tumor invasion (Pullman et al., 1998). A 9.5 kb deletion involving a previously and Bodmer, 1992). A set of PCR primers, c1 and c2, identified partial transcript from 16qter was discovered were designed from the original open reading frame in all affected individuals from a 16q24.3-linked family. sequence (Pullman and Bodmer, 1992) and tested on In addition, two frameshift mutations, both generating all individuals from our HSP family. As shown in Figure truncated forms of the protein, were found in a French 1A, the five affected individuals failed to amplify, while family with a complicated form of HSP and in another healthy sibs and parents yielded the expected PCR Italian family with pure HSP. BLAST analysis revealed product. This result was replicated with a different set that this gene encodes a novel protein, which we named of primers, c3 and c4, from the same transcript (data Paraplegin, highly homologous to a subclass of yeast not shown). Consequently, a homozygous deletion mitochondrial metalloproteases. Immunofluorescence spanning this gene was hypothesized, consistent with analysis in transfected COS-7 cells and mitochondrial the finding of a homozygous haplotype for 16qter mark- import in vitro experiments showed a specific mitochon- ers displayed by the affected individuals (De Michele et drial sublocalization. Analysis of muscle biopsy speci- al., 1998). mens from two HSP patients carrying Paraplegin muta- Several ESTs identical to the reported CMAR se- tions showed the presence of typical signs of OXPHOS quence were found in dbEST, allowing us to build a impairment. 1.1 kb cDNA contig and extending the original 459 bp These data demonstrate an abnormality in a nuclear- sequence toward the 59 end. We selected a few clones, encoded mitochondrial protein and the presence of mi- namely, 154385, 154386 and 31543, which were rese- tochondrial OXPHOS defects in HSP, revealing the pres- quenced either partially or completely (clone 154386), confirming the sequence data reported in dbEST. The ence of an impairment of mitochondrial function in this entire 1.1 kb insert fragment of EST clone 154386 was class of progressive neurodegenerative disorders. used as a probe on an EcoRI-restricted Southern blot containing DNA from one patient and a control. Figure Results 1B shows the absence of a 5.6 kb EcoRI band in the patient DNA, thus confirming the presence of a homozy- A 9.5 kb Deletion of Chromosome 16q24.3 in HSP gous deletion. Recently, we described a large consanguineous Italian To determine the extent of the 16q24.3 deletion in family affected by autosomal recessive HSP (family 1). HSP patients, an arrayed human genomic PAC library Patients from this family showed typical features of the (Ioannou and de Jong, 1996) was probed with PCR frag- pure form of HSP, with age of onset ranging from 25 to ments c1-c2 and c3-c4, spanning from nucleotide 2881 42 and a slow progression of symptoms. A genome- to 3016 and from 2524 to 2856 of the cDNA sequence, wide search using a panel of 358 highly polymorphic respectively. One positive clone, 1194G18, was identi- microsatellite markers showed linkage of the disease fied by hybridization screening and confirmed by c1-c2 locus in this family to markers on chromosome 16q24.3 and c3-c4 PCR amplification. Alu-vector-specific PCR in a region spanning approximately 6 cM from D16S3048 primers (see Experimental Procedures) allowed us to to the telomere (De Michele et al., 1998). This region sequence the ends of the human genomic PAC insert included several human ESTs as well as some known and design two sets of primers at each end of the PAC Mitochondrial Metalloprotease Mutations in HSP 975 Figure 2.
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