ALS5/SPG11/<i>KIAA1840</i>mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

Montecchiani, Celeste; Pedace, Lucia; Giudice, Temistocle Lo; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José Luiz; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; George-Hyslop, Peter St; Barsottini, Orlando Graziani Póvoas; Kawarai, Toshitaka; Orlacchio, Antonio

doi:10.1093/brain/awv320

Cited by 80 publications

(60 citation statements)

References 73 publications

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“…Mutations in E2 cause Charcot-Marie-Tooth disease type 2R characterized by muscle weakness, atrophy, and axonal degeneration [41]. As early as 8 weeks of age, Cardinet et al .…”

Section: Discussionmentioning

confidence: 99%

A novel iterative mixed model to remap three complex orthopedic traits in dogs

et al. 2017

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Hip dysplasia (HD), elbow dysplasia (ED), and rupture of the cranial (anterior) cruciate ligament (RCCL) are the most common complex orthopedic traits of dogs and all result in debilitating osteoarthritis. We reanalyzed previously reported data: the Norberg angle (a quantitative measure of HD) in 921 dogs, ED in 113 cases and 633 controls, and RCCL in 271 cases and 399 controls and their genotypes at ~185,000 single nucleotide polymorphisms. A novel fixed and random model with a circulating probability unification (FarmCPU) function, with marker-based principal components and a kinship matrix to correct for population stratification, was used. A Bonferroni correction at p<0.01 resulted in a P< 6.96 ×10−8. Six loci were identified; three for HD and three for RCCL. An associated locus at CFA28:34,369,342 for HD was described previously in the same dogs using a conventional mixed model. No loci were identified for RCCL in the previous report but the two loci for ED in the previous report did not reach genome-wide significance using the FarmCPU model. These results were supported by simulation which demonstrated that the FarmCPU held no power advantage over the linear mixed model for the ED sample but provided additional power for the HD and RCCL samples. Candidate genes for HD and RCCL are discussed. When using FarmCPU software, we recommend a resampling test, that a positive control be used to determine the optimum pseudo quantitative trait nucleotide-based covariate structure of the model, and a negative control be used consisting of permutation testing and the identical resampling test as for the non-permuted phenotypes.

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“…Mutations in E2 cause Charcot-Marie-Tooth disease type 2R characterized by muscle weakness, atrophy, and axonal degeneration [41]. As early as 8 weeks of age, Cardinet et al .…”

Section: Discussionmentioning

confidence: 99%

A novel iterative mixed model to remap three complex orthopedic traits in dogs

et al. 2017

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“…Although human disease-causing mutations have not yet been attributed to mutations in Zfp106 (ZNF106 in humans), it is notable that the human ZNF106 locus resides within a region of chromosome 15 that is associated with both a juvenile recessive form of amyotrophic lateral sclerosis (ALS5) and axonal autosomal-recessive Charcot-Marie Tooth disease (CMT2X) (59,60). Mutations in Spatacsin (SPG11), a gene first associated with spastic paraplegia, have been associated with patients with ALS5 or CMT2X (61).…”

Section: Discussionmentioning

confidence: 99%

Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106

Anderson

Cannavino

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve-muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.ZNF106 | amyotrophic lateral sclerosis (ALS) | neuromuscular junction (NMJ) | motor neuron disease (MND) | pre-mRNA splicing S ignaling between the presynaptic terminus of a motor neuron and the postsynaptic membrane of a skeletal myofiber occurs at the neuromuscular junction (NMJ), the site of communication that allows for neural control of myofiber identity, growth, and contractility (1). Motor neuron damage or perturbation of nervemuscle signaling through disruption of the NMJ causes a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and hereditary spastic paraplegia (HSP) (2-6). These neurodegenerative diseases are genetically heterogeneous, with mutations in proteins associated with diverse cellular and molecular functions (7)(8)(9)(10). Although the precise disease mechanisms underlying the pathogenesis of these disorders remain unclear, abnormalities in apoptotic signaling, oxidative stress, protein folding, and RNA processing in motor neurons and skeletal muscle have been implicated in these diseases (11)(12)(13)(14)(15).In a bioinformatics screen for nuclear proteins with enriched expression in skeletal muscle, we identified ZFP106, a zinc finger protein first characterized as an immunodominant cytotoxic determinant of the mouse H3 minor histocompatibility complex (16,17). Zinc fingers (ZnFs) mediate DNA, RNA, and protein interactions and are commonly found in regulatory proteins that govern gen...

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“…Finally, a group of recessive spastic paraplegia genes associated with a thin corpus callosum on MRI have recently been identified as a cause of neuropathy spasticity syndromes. SPG11 is the most common of these syndromes and presents with spastic paraplegia, cognitive decline, sensory and motor axonal neuropathy and often weight gain40; patients with SPG15 have a similar phenotype but with pigmentary maculopathy41; SPG46 is a similar disease to SPG11 but with cataracts 42…”

Section: Introductionmentioning

confidence: 99%

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis

Rossor

Carr

Devine

et al. 2017

J Neurol Neurosurg Psychiatry

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Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy e.g. spasticity, the type of neuropathy, and the other neurological and nonneurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories -1) ataxia, 2) spasticity, and 3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy e.g. cardiomyopathy and neuropathy. We also include a separate category of complex inherited relapsing neuropathy syndromes, some of which may mimic Guillain Barré syndrome, as many will have a metabolic aetiology and be potentially treatable.

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ALS5/SPG11/KIAA1840mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

Cited by 80 publications

References 73 publications

A novel iterative mixed model to remap three complex orthopedic traits in dogs

A novel iterative mixed model to remap three complex orthopedic traits in dogs

Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis

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