Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers

Hentati, Afif; Ouahchi, Karim; Pericak‐Vance, Margaret A.; Nijhawan, Deepak; Ahmad, Arsalan; Yang, Yi; Rimmler, Jacqueline; Hung, Wu Yen; Schlotter, Beate; Ahmed, Akhtar; Hamida, M. Ben; Hentati, Fayçal; Siddique, Teepu

doi:10.1007/s100480050052

Cited by 158 publications

(70 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.

View full text Add to dashboard Cite

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...

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…Several mutations in this gene cause slowly progressive juvenile ALS. Additional genes are being identified (7)(8)(9). Animal studies suggest more gene mutations that may cause human ALS, including neurofilaments (10), dynein (11), dynamitin (12), tubulin chaperon (13,14), and vegf (15).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Tummala

Jung

Tiwari

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, paralysis, and death. Mutant Cu,Znsuperoxide dismutase (SOD1) causes a subset of ALS by an unidentified toxic property. Increasing evidence suggests that chaperone dysfunction plays a role in motor neuron degeneration in ALS. To investigate the relationship between mutant SOD1 expression and chaperone dysfunction, we measured chaperone function in central nervous system tissue lysates from normal mice and transgenic mice expressing human SOD1 variants. We observed a significant decrease in chaperone activity in tissues from mice expressing ALS-linked mutant SOD1 but not control mice expressing human wild type SOD1. This decrease was detected only in the spinal cord, became apparent by 60 days of age (before the onset of muscle weakness and significant motor neuron loss), and persisted throughout the late stages. In addition, this impairment of chaperone activity occurred only in cytosolic but not in mitochondrial and nuclear fractions. Furthermore, multiple recombinant human SOD1 mutants with differing biochemical and biophysical properties inhibited chaperone function in a cell-free extract of normal mouse spinal cords. Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins.

show abstract

“…The study of three consanguineous Tunisian pedigrees originally established linkage of chr15q15-q21 to an autosomal recessive form of ALS (Hentati et al 1998). A more recent study of 25 unrelated FALS families revealed 10 pedigrees with linkage to the same region and disease associated mutations in the spatacsin (SPG11) gene (Orlacchio et al 2010).…”

Section: Genetic Loci Linked To Als 361 Als5: Spatacsin (Spg11)mentioning

confidence: 99%

“…Clinically, FALS patients with linkage to this region experience a juvenile onset, slowly progressive motor neuropathy associated with both upper and lower motor neurone signs. Disease duration is typically over 10-40 years without sensory symptoms and an absence of the feature of thin corpus callosum (Hentati et al 1998;Orlacchio et al 2010). Mutations in this gene have been previously found to be the most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC), a condition characterised by progressive spasticity of lower limbs, mild cognitive impairment and a thin, but otherwise normally structured, corpus callosum (Abdel Aleem et al 2011).…”

Section: Genetic Loci Linked To Als 361 Als5: Spatacsin (Spg11)mentioning

confidence: 99%

Genetics of Familial Amyotrophic Lateral Sclerosis

Goodall¹,

Bury²,

Cooper‐Knock³

et al. 2012

Amyotrophic Lateral Sclerosis

View full text Add to dashboard Cite

Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers

Cited by 158 publications

References 14 publications

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

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

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Genetics of Familial Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About