Focus on SPG11 HSP - HSP Research Foundation

Large study of gene causing SPG11 HSP

Causes HSP, CMT and ALS

SPG11 is the causative gene of a wide spectrum of clinical features, including autosomal recessive HSP, axonal Charcot-Marie-Tooth disease (CMT) and Motor Neurone Disease (ALS/MND).

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained.

Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease.

We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6).

Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan.

Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.

SOURCE: Brain. 2015 Nov 10. pii: awv320. [Epub ahead of print] © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. PMID: 26556829 [PubMed – as supplied by publisher]

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

Montecchiani C1, Pedace L1, Lo Giudice T2, Casella A1, Mearini M1, Gaudiello F1, Pedroso JL3, Terracciano C4, Caltagirone C5, Massa R4, St George-Hyslop PH6, Barsottini OG3, Kawarai T7, Orlacchio A8.

11 Laboratorio di Neurogenetica, CERC – IRCCS Santa Lucia, Rome, Italy.

21 Laboratorio di Neurogenetica, CERC – IRCCS Santa Lucia, Rome, Italy 2 Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy.

33 Department of Neurology, Universidade Federal de São Paulo, Brazil.

42 Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy.

52 Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy 4 Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy.

65 Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada 6 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 7 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

78 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

81 Laboratorio di Neurogenetica, CERC – IRCCS Santa Lucia, Rome, Italy 2 Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy [email protected].

SPG11 mechanism investigated further

Vital role of lysosomes identified

Cell organelles called lysosomes are reduced in number in the cortical neurons and other types of brain cells in SPG11 HSP. This results in a chain reaction leading to a failure to remove waste products, leading to the death of these brain cells.

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear.

Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation.

Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

SOURCE: PLoS Genet. 2015 Aug 18;11(8):e1005454. doi: 10.1371/journal.pgen.1005454. eCollection 2015. PMID: 26284655 [PubMed – in process] PMCID: PMC4540459

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

Varga RE1, Khundadze M2, Damme M3, Nietzsche S4, Hoffmann B5, Stauber T6, Koch N7, Hennings JC2, Franzka P2, Huebner AK2, Kessels MM7, Biskup C5, Jentsch TJ6, Qualmann B7, Braulke T8, Kurth I2, Beetz C9, Hübner CA2.

1Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany; Institute of Clinical Chemistry, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

2Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

3Biochemical Institute, University of Kiel, Kiel, Germany.

4Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

5Biomolecular Photonics Group, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

6Leibniz-Institut für Molekulare Pharmakologie (FMP) und Max-Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany.

7Institute of Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

8Department of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

9Institute of Clinical Chemistry, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

SPG11 HSP spectrum keeps expanding

Now identified with a cholesterol disorder

SPG11 HSP, a well-known cause of complicated HSP, has now been found in a Turkish family associated with a disorder in LDL cholesterol levels.

A 24-year-old male presented with progressive gait disturbance and was diagnosed with hereditary spastic paraplegia. His brother and possibly one uncle also had the condition. Routine biochemical testing found that the patient had unusually low plasma concentrations of low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B, the hallmark of familial hypobetalipoproteinemia. DNA sequencing showed that he, along with other family members (n=5; mean LDL cholesterol 0.8 mmol/L, apoB 0.31 g/L), were heterozygous for a single nucleotide deletion in exon 26 of the APOB gene. This mutation is predicted to form a truncated apoB species of 3545 amino acids, which we have designated apoB-78.2.

SOURCE: Clinica Chimica Acta (Impact Factor: 2.82). 05/2008; 390(1-2):152-5. DOI: 10.1016/j.cca.2008.01.021

SPG11 mutation in a Turkish familial hypobetalipoproteinemia family with hereditary spastic paraplegia

Hooper AJ1, Akinci B2, Davis MR3, Burnett JR4.

1Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital; University of Western Australia, Perth, Australia.

2Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Dokuz Eylul, Izmir, Turkey.

3Neurogenetics Laboratory, Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Perth Australia.

4Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital; University of Western Australia, Perth, Australia. Electronic address: [email protected].

Dear Editor,

We previously reported a unique case of heterozygous familial hypobetalipoproteinemia due to an apoB-78.2 mutation together with hereditary spastic paraplegia (HSP) in a Turkish proband [1]. The HSPs are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs [2]. Over 55 spastic paraplegia genes have been identified, with autosomal dominant, autosomal recessive, and X-linked modes of inheritance described. HSP can be described as ‘complicated’, where the HSP occurs together with cognitive impairment, ataxia, peripheral neuropathy, deafness, cataracts or muscle atrophy, or ‘pure’ or ‘uncomplicated’, which is diagnosed in the absence of these additional abnormalities [3].

In our case, HSP affected the proband and his brother, and possibly an uncle, who was deceased. At the time, we sequenced the PLP1 gene to exclude it as an X-linked cause of HSP, but could not exclude an autosomal recessive HSP given the consanguineous marriage between the proband’s parents. Recently, we used next-generation sequencing to analyse a neuromuscular gene panel in the proband and were able to identify a homozygous c.5255de1T (p.Phe1752fs) mutation in exon 30 of the SPG11 gene (NM_025137.3). Sanger sequencing confirmed the homozygous mutation in the proband and brother, and the parents as heterozygous carriers. SPG11 encodes the protein spatacsin, which is ubiquitously expressed in the nervous system, and is important for early neuronal development and survival [4]. Frameshift, nonsense and splicing mutations throughout the gene cause autosomal recessive HSP associated with severe motor and cognitive impairment [5]. SPG11 mutations are a common cause of autosomal recessive HSP; in a cohort of ‘complicated’ HSP patients of German and Turkish descent, SPG11 mutations were found in 14% [6].