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Erschienen in: Journal of Neurology 2/2014

01.02.2014 | Original Communication

Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis

verfasst von: Andrea Citterio, Alessia Arnoldi, Elena Panzeri, Maria Grazia D’Angelo, Massimiliano Filosto, Robertino Dilena, Filippo Arrigoni, Marianna Castelli, Cristina Maghini, Chiara Germiniasi, Francesca Menni, Andrea Martinuzzi, Nereo Bresolin, Maria Teresa Bassi

Erschienen in: Journal of Neurology | Ausgabe 2/2014

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Abstract

Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.
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Literatur
5.
6.
Zurück zum Zitat Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G (2012) Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci 318(1–2):1–18. doi:10.1016/j.jns.2012.03.025 CrossRefPubMed Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G (2012) Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci 318(1–2):1–18. doi:10.​1016/​j.​jns.​2012.​03.​025 CrossRefPubMed
7.
Zurück zum Zitat Tesson C, Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, Schule R, Mignot C, Obre E, Bouhouche A, Santorelli FM, Durand CM, Oteyza AC, El-Hachimi KH, Al Drees A, Bouslam N, Lamari F, Elmalik SA, Kabiraj MM, Seidahmed MZ, Esteves T, Gaussen M, Monin ML, Gyapay G, Lechner D, Gonzalez M, Depienne C, Mochel F, Lavie J, Schols L, Lacombe D, Yahyaoui M, Al Abdulkareem I, Zuchner S, Yamashita A, Benomar A, Goizet C, Durr A, Gleeson JG, Darios F, Brice A, Stevanin G (2012) Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 91(6):1051–1064. doi:10.1016/j.ajhg.2012.11.001 PubMedCentralCrossRefPubMed Tesson C, Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, Schule R, Mignot C, Obre E, Bouhouche A, Santorelli FM, Durand CM, Oteyza AC, El-Hachimi KH, Al Drees A, Bouslam N, Lamari F, Elmalik SA, Kabiraj MM, Seidahmed MZ, Esteves T, Gaussen M, Monin ML, Gyapay G, Lechner D, Gonzalez M, Depienne C, Mochel F, Lavie J, Schols L, Lacombe D, Yahyaoui M, Al Abdulkareem I, Zuchner S, Yamashita A, Benomar A, Goizet C, Durr A, Gleeson JG, Darios F, Brice A, Stevanin G (2012) Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 91(6):1051–1064. doi:10.​1016/​j.​ajhg.​2012.​11.​001 PubMedCentralCrossRefPubMed
8.
Zurück zum Zitat Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J; FORGE Canada Consortium, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP (2012) Mutations in DDHD2, encoding an intracellular phospholipase A (1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 91(6):1073–1081. doi:10.1016/j.ajhg.2012.10.017 CrossRef Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J; FORGE Canada Consortium, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP (2012) Mutations in DDHD2, encoding an intracellular phospholipase A (1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 91(6):1073–1081. doi:10.​1016/​j.​ajhg.​2012.​10.​017 CrossRef
9.
Zurück zum Zitat Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D (2012) Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet 91(6):1065–1072. doi:10.1016/j.ajhg.2012.09.015 PubMedCentralCrossRefPubMed Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D (2012) Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet 91(6):1065–1072. doi:10.​1016/​j.​ajhg.​2012.​09.​015 PubMedCentralCrossRefPubMed
10.
Zurück zum Zitat Martin E, Schüle R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schöls L, Mhiri C, Lamari F, Züchner S, De Jonghe P, Kabashi E, Brice A, Stevanin G (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 92(2):238–244. doi:10.1016/j.ajhg.2012.11.021 PubMedCentralCrossRefPubMed Martin E, Schüle R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schöls L, Mhiri C, Lamari F, Züchner S, De Jonghe P, Kabashi E, Brice A, Stevanin G (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 92(2):238–244. doi:10.​1016/​j.​ajhg.​2012.​11.​021 PubMedCentralCrossRefPubMed
11.
Zurück zum Zitat Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92(2):245–251. doi:10.1016/j.ajhg.2012.12.012 PubMedCentralCrossRefPubMed Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92(2):245–251. doi:10.​1016/​j.​ajhg.​2012.​12.​012 PubMedCentralCrossRefPubMed
12.
Zurück zum Zitat Goizet C, Boukhris A, Maltete D, Guyant-Maréchal L, Truchetto J, Mundwiller E, Hanein S, Jonveaux P, Roelens F, Loureiro J, Godet E, Forlani S, Melki J, Auer-Grumbach M, Fernandez JC, Martin-Hardy P, Sibon I, Sole G, Orignac I, Mhiri C, Coutinho P, Durr A, Brice A, Stevanin G (2009) SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73(14):1111–1119. doi:10.1212/WNL.0b013e3181bacf59 CrossRefPubMed Goizet C, Boukhris A, Maltete D, Guyant-Maréchal L, Truchetto J, Mundwiller E, Hanein S, Jonveaux P, Roelens F, Loureiro J, Godet E, Forlani S, Melki J, Auer-Grumbach M, Fernandez JC, Martin-Hardy P, Sibon I, Sole G, Orignac I, Mhiri C, Coutinho P, Durr A, Brice A, Stevanin G (2009) SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73(14):1111–1119. doi:10.​1212/​WNL.​0b013e3181bacf59​ CrossRefPubMed
13.
Zurück zum Zitat Schüle R, Schlipf N, Synofzik M, Klebe S, Klimpe S, Hehr U, Winner B, Lindig T, Dotzer A, Riess O, Winkler J, Schöls L, Bauer P (2009) Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 80(12):1402–1404. doi:10.1136/jnnp.2008.167528 CrossRefPubMed Schüle R, Schlipf N, Synofzik M, Klebe S, Klimpe S, Hehr U, Winner B, Lindig T, Dotzer A, Riess O, Winkler J, Schöls L, Bauer P (2009) Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 80(12):1402–1404. doi:10.​1136/​jnnp.​2008.​167528 CrossRefPubMed
16.
Zurück zum Zitat Körschen HG, Yildiz Y, Raju DN, Schonauer S, Bönigk W, Jansen V, Kremmer E, Kaupp UB, Wachten D (2013) The non-lysosomal β-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi. J Biol Chem 288(5):3381–3393. doi:10.1074/jbc.M112.414714 PubMedCentralCrossRefPubMed Körschen HG, Yildiz Y, Raju DN, Schonauer S, Bönigk W, Jansen V, Kremmer E, Kaupp UB, Wachten D (2013) The non-lysosomal β-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi. J Biol Chem 288(5):3381–3393. doi:10.​1074/​jbc.​M112.​414714 PubMedCentralCrossRefPubMed
17.
Zurück zum Zitat Gonzalez M, Nampoothiri S, Kornblum C, Oteyza AC, Walter J, Konidari I, Hulme W, Speziani F, Schöls L, Züchner S, Schüle R (2013) Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). Eur J Hum Genet 21(11):1214–1218. doi:10.1038/ejhg.2013.29 PubMedCentralCrossRefPubMed Gonzalez M, Nampoothiri S, Kornblum C, Oteyza AC, Walter J, Konidari I, Hulme W, Speziani F, Schöls L, Züchner S, Schüle R (2013) Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). Eur J Hum Genet 21(11):1214–1218. doi:10.​1038/​ejhg.​2013.​29 PubMedCentralCrossRefPubMed
18.
Zurück zum Zitat Inoue H, Baba T, Sato S, Ohtsuki R, Takemori A, Watanabe T, Tagaya M (1823) Tani K (2012) Roles of SAM and DDHD domains in mammalian intracellular phospholipase A1 KIAA0725p. Biochim Biophys Acta 4:930–939. doi:10.1016/j.bbamcr.2012.02.002 Inoue H, Baba T, Sato S, Ohtsuki R, Takemori A, Watanabe T, Tagaya M (1823) Tani K (2012) Roles of SAM and DDHD domains in mammalian intracellular phospholipase A1 KIAA0725p. Biochim Biophys Acta 4:930–939. doi:10.​1016/​j.​bbamcr.​2012.​02.​002
19.
Zurück zum Zitat Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Augé A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G (2010) A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics 11(4):441–448. doi:10.1007/s10048-010-0249-2 CrossRefPubMed Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Augé A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G (2010) A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics 11(4):441–448. doi:10.​1007/​s10048-010-0249-2 CrossRefPubMed
20.
Zurück zum Zitat Boot RG, Verhoek M, Donker-Koopman W, Strijland A, van Marle J, Overkleeft HS, Wennekes T (2007) Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem 282(2):1305–1312. doi:10.1074/jbc.M610544200 CrossRefPubMed Boot RG, Verhoek M, Donker-Koopman W, Strijland A, van Marle J, Overkleeft HS, Wennekes T (2007) Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem 282(2):1305–1312. doi:10.​1074/​jbc.​M610544200 CrossRefPubMed
21.
Zurück zum Zitat Yildiz Y, Matern H, Thompson B, Allegood JC, Warren RL, Ramirez DM, Hammer RE, Hamra FK, Matern S, Russell DW (2006) Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest 116(11):2985–2994. doi:10.1172/JCI29224 PubMedCentralCrossRefPubMed Yildiz Y, Matern H, Thompson B, Allegood JC, Warren RL, Ramirez DM, Hammer RE, Hamra FK, Matern S, Russell DW (2006) Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest 116(11):2985–2994. doi:10.​1172/​JCI29224 PubMedCentralCrossRefPubMed
Metadaten
Titel
Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis
verfasst von
Andrea Citterio
Alessia Arnoldi
Elena Panzeri
Maria Grazia D’Angelo
Massimiliano Filosto
Robertino Dilena
Filippo Arrigoni
Marianna Castelli
Cristina Maghini
Chiara Germiniasi
Francesca Menni
Andrea Martinuzzi
Nereo Bresolin
Maria Teresa Bassi
Publikationsdatum
01.02.2014
Verlag
Springer Berlin Heidelberg
Erschienen in
Journal of Neurology / Ausgabe 2/2014
Print ISSN: 0340-5354
Elektronische ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-013-7206-6

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