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Mutations in SPG11, Encoding Spatacsin, Are a Major Cause of Spastic Paraplegia with Thin Corpus Callosum

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Mutations in SPG11, Encoding Spatacsin, Are a Major Cause of Spastic Paraplegia with Thin Corpus Callosum LETTERS Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum Giovanni Stevanin1–3,17, Filippo M Santorelli4,17, Hamid Azzedine1,2,17, Paula Coutinho5,6, Jacques Chomilier7, Paola S Denora4, Elodie Martin1,2, Anne-Marie Ouvrard-Hernandez8, Alessandra Tessa4,Naı¨ma Bouslam1,2, Alexander Lossos9, Perrine Charles3,Jose´ L Loureiro5,6, Nizar Elleuch1,2, Christian Confavreux10, Vı´tor T Cruz6, Merle Ruberg1,2, Eric Leguern1–3, Djamel Grid11, Meriem Tazir12, Bertrand Fontaine13–15, Alessandro Filla16, Enrico Bertini4, Alexandra Durr1–3 & Alexis Brice1–3,14,15 http://www.nature.com/naturegenetics Autosomal recessive hereditary spastic paraplegia (ARHSP) The major ARHSP-TCC locus, SPG11 (refs. 4–6), was recently with thin corpus callosum (TCC) is a common and clinically restricted to the region between markers D15S968 and D15S132 distinct form of familial spastic paraplegia that is linked to the (refs. 7–9). This disorder is found in several ethnic groups, particularly SPG11 locus on chromosome 15 in most affected families. in countries around the Mediterranean basin and in Japan5–9. TCC is We analyzed 12 ARHSP-TCC families, refined the SPG11 not restricted to SPG11, however10–13. candidate interval and identified ten mutations in a previously In the current study, all available members of 12 ARHSP-TCC unidentified gene expressed ubiquitously in the nervous system families were genotyped using 34 microsatellite markers in the but most prominently in the cerebellum, cerebral cortex, candidate interval for SPG11 and the adjacent and overlapping loci hippocampus and pineal gland. The mutations were either for SPG21 (ref. 12) and agenesis of corpus callosum with polyneuro- nonsense or insertions and deletions leading to a frameshift, pathy (ACCPN)14. Maximal positive multipoint LOD scores ranging suggesting a loss-of-function mechanism. The identification from 0.60 to 3.85, which corresponded to the maximal expected values Nature Publishing Group Group Nature Publishing 7 of the function of the gene will provide insight into the in the pedigrees, were obtained in ten families in the SPG11 interval 200 mechanisms leading to the degeneration of the corticospinal (Supplementary Fig. 1 online). The combined multipoint LOD score © tract and other brain structures in this frequent form reached the value of 17.32 in these families. Linkage was not of ARHSP. conclusive in the two remaining kindreds. Haplotype reconstructions in two consanguineous families (FSP672 and FSP221) with strong ARHSP-TCC clinically manifests as spastic paraplegia, usually begin- evidence for linkage to SPG11 (LOD scores of 2.60 and 3.85) further ning during infancy or puberty (and up to 23 years), preceded by restricted the region most likely to contain the responsible gene to learning difficulties1–3. Cognitive impairment is first noticed in child- the 3.2-cM homozygous region between D15S778 and D15S659 hood and progresses insidiously to severe functional disability of a (Supplementary Figs. 1 and 2 online). This was the only region frontal type over a period of 10–20 years2. Some affected individuals that segregated with the disease in a genome scan performed in the develop a pseudobulbar involvement, with dysarthria, dysphagia and most informative family (FSP221). upper limb spasticity, associated with bladder dysfunction and signs of This interval contains B40 genes, according to the National Center predominantly axonal, motor or sensorimotor peripheral neuropa- for Biotechnology Information (NCBI) and Ensembl databases. We thy3. Positron emission tomography shows cortical and thalamic analyzed 18 genes (Fig. 1) in SPG11 index patients by direct sequenc- glucose hypometabolism. Magnetic resonance imaging shows TCC ing of all exons and their splicing sites but did not find any disease- that predominates in the rostral third, with hyperintensities in causing mutations in 17 of them. When we analyzed the KIAA1840 periventricular white matter and cerebral cortical atrophy predomi- gene, also known as FLJ21439, we found ten different mutations in 11 nating in the frontal region. of these families (Fig. 1b). All mutations (four nonsense mutations, 1INSERM, UMR679, Federal Institute for Neuroscience Research, Pitie´-Salpeˆtrie`re Hospital, Paris, France. 2Universite´ Pierre et Marie Curie-Paris 6, UMR679, Pitie´- Salpeˆtrie`re Hospital, Paris, France. 3Assistance Publique–Hoˆpitaux de Paris (AP-HP), Pitie´-Salpeˆtrie`re Hospital, Department Cytogenetics and Genetics, Paris, France. 4Unit of Molecular Medicine, IRCCS-Bambino Gesu` Children’s Hospital, Rome, Italy. 5UnIGENe, University of Porto, Portugal. 6Departamento de Neurologia, Hospital S. Sebastiao, Santa Maria da Feira, Portugal. 7Institut de Mine´ralogie et de Physique des Milieux Condense´s, Paris 6 and 7 Universities, Paris, France. 8Department of Neurology, Centre Hospitalier Universitaire, Grenoble, France. 9Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 10Hoˆpital Neurologique et Neurochirurgical Pierre Wertheimer, Lyon, France. 11Genethon, Evry, France. 12Department of Neurology, Mustapha Hospital, Algiers, Algeria. 13INSERM U546, Salpeˆtrie`re Hospital, Paris, France. 14AP-HP, Pitie´-Salpeˆtrie`re Hospital, Federation of Neurology, Paris, France. 15Universite´ Pierre et Marie Curie-Paris 6, Pitie´-Salpeˆtrie`re Medical School, Paris, France. 16Department of Neurological Sciences, Federico II University, Naples, Italy. 17These authors contributed equally to this work. Correspondence should be addressed to G.S. ([email protected]). Received 26 July 2006; accepted 18 January 2007; published online 18 February 2007; doi:10.1038/ng1980 366 VOLUME 39 [ NUMBER 3 [ MARCH 2007 NATURE GENETICS LETTERS Figure 1 Critical region of SPG11.(a) Physical a map of human chromosome 15q15–21 with selected genetic markers and the candidate D15S779 D15S780 D15S515D15S778 D15S783D15S781D15S537D15S516D15S517D15S172D15S1508 D15S659 D15S132 D15S161D15S143D15S123 genes that were sequenced. Distances in Mb are 41 42 43 44 45 Mb indicated relative to chromosome 15 according to the Ensembl database. Markers defining MAP1A#> CTDSPL2> SORD> <SLC30A4 the reduced candidate interval are in bold. # <TTBK2 CKMT1> SEMA6D > <ELL3 EIF3S1> <DUOX2 PLDN> # indicates that these genes (SEMA6D and 8 DUOX1> SPATA5L1> MAP1A) were analyzed in a previous study . < STRC <MFAP1 < KIAA1840 4 and o indicate the orientation of the open SLC28A2> <CATSPER2 200 kb reading frame (ORF) of each gene. (b)Exon- Mutations intron structure of the 101 kb of the KIAA1840 Nucleotide position gene, also known as FLJ21439, with positions Protein position of mutations identified in 11 SPG11 families. Family or families (c) Several of the putative functional domains with mutation (boxes) and their positions on the protein b sequence. Regions I and II correspond to 733_734delAT 1203delA 2842_2843insG 5974C>T structurally similar domains based on their M245VfsX K401KfsX V948GfsX R1992X hydrophobicity status analyzed with DrawHCA FSP117 PE PE FSP117 software. Notably, this protein is assigned to 1 5 10 15 20 25 30 35 40 Exons the aromatic compound dioxygenase superfamily because of a 22% identity with the consensus ATG X sequence between residues 2104 and (7322bp) 2381 (ref. 24). 6100C>T 118C>T 2198T>G 7029_7030insT R2034X Q40X L733X V2344CfsX http://www.nature.com/naturegenetics FSP221 FSP672 529_533delATATT OS FSP515 of progressive and severe spastic paraplegia I177_I178delfsX FSP732 with distal wasting and cognitive problems FSP386 FSP446 6451delG FSP754 A2151PfsX (Table 1). In several cases (n ¼ 6), cognitive SAL1608 dysfunction clearly worsened with disease Glycosyl Coil-coil Myb progression. Cerebral imaging showed a c hydroxylase F1 Leucine domain domain signature zipper TCC accompanied by periventricular white 482 611 1556 1766 matter changes and cortical atrophy in the 490 632 1590 1774 majority of affected individuals. Pseudobul- 1 2443 amino 163 1239 200 1471 acids bar dysarthria was frequent (54%, n ¼ 12), I II 194 240 560-700 1267 1493 2250-2390 and dystonic voice was noted in one TM TM TM TM individual. Notably, although electro- Nature Publishing Group Group Nature Publishing 7 myographic recordings were normal in a few affected individuals, peripheral neuropa- 200 © four small deletions and two small insertions) were in the coding thy was frequent (72%, 13/18) and was mostly associated with pure sequence and were at the homozygous state, except in two kindreds in motor changes. We occasionally observed additional signs, such which affected individuals were compound heterozygous for two as optic atrophy, retinitis pigmentosa, mild cerebellar signs, cataract different variants in this gene. Mutations segregated with the disease and clinodactyly. in all families (Fig. 2a,b,c) and were not detected in a panel of at The human SPG11 gene contains 40 exons on chromosome least 140 chromosomes from unrelated control individuals of 15q21.1. The full-length 8-kb transcript encodes a predicted protein European or North African origin. All were predicted to cause early of 2,443 amino acids of unknown function, which we termed protein truncation. spatacsin, after ‘spasticity with thin or atrophied corpus callosum We found only two mutations in more than one pedigree syndrome protein’. The sequence of spatacsin has been strongly (Fig. 2a,b). We identified a homozygous 6100C-T substitution conserved throughout evolution, with orthologs in mammals
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