A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy

AbstractA juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.

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PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

Genes ◽

10.3390/genes12101489 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1489

Author(s):

Gabriela Rudd Garces ◽

Maria Elena Turba ◽

Myriam Muracchini ◽

Alessia Diana ◽

Vidhya Jagannathan ◽

...

Keyword(s):

Autosomal Recessive ◽

Donor Site ◽

Genetic Defect ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Splice Donor Site ◽

Loss Of Function ◽

Gene Encoding ◽

Encoding Protein

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634 + 1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.

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YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Genes ◽

10.3390/genes11030313 ◽

2020 ◽

Vol 11 (3) ◽

pp. 313

Author(s):

Corinne Gurtner ◽

Petra Hug ◽

Miriam Kleiter ◽

Kernt Köhler ◽

Elisabeth Dietschi ◽

...

Keyword(s):

Genetic Defect ◽

Autosomal Recessive Inheritance ◽

Missense Variant ◽

Homozygosity Mapping ◽

Pedigree Analysis ◽

Trna Synthetase ◽

Loss Of Function ◽

Juvenile Mortality ◽

Abnormal Accumulation ◽

The Central Nervous System

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

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The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells10081865 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1865

Author(s):

Nica Borgese ◽

Nicola Iacomino ◽

Sara Francesca Colombo ◽

Francesca Navone

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Adaptor Proteins ◽

Loss Of Function ◽

Membrane Contact Sites ◽

Physiological Processes ◽

Main Driver ◽

Single Allele ◽

Induced Pluripotent ◽

Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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“My World Has Expanded Even Though I'm Stuck at Home”: Experiences of Individuals With Amyotrophic Lateral Sclerosis Who Use Augmentative and Alternative Communication and Social Media

American Journal of Speech-Language Pathology ◽

10.1044/2015_ajslp-15-0010 ◽

2015 ◽

Vol 24 (4) ◽

pp. 680-695 ◽

Cited By ~ 22

Author(s):

Jessica Caron ◽

Janice Light

Keyword(s):

Social Media ◽

Amyotrophic Lateral Sclerosis ◽

Augmentative And Alternative Communication ◽

Future Research ◽

Loss Of Function ◽

Alternative Communication ◽

Communication Modes ◽

Communication Needs ◽

Use Of Social Media ◽

Lateral Sclerosis

PurposeThis study aimed to expand the current understanding of how persons with amyotrophic lateral sclerosis (pALS) use augmentative and alternative communication and social media to address their communication needs.MethodAn online focus group was used to investigate the experiences of 9 pALS who use augmentative and alternative communication and social media. Questions posed to the group related to (a) current use of social media, (b) advantages of social media, (c) barriers to independent use, (d) supports to independent use, and (e) recommendations for developers, policy makers, and other pALS.ResultsParticipants primarily reported that use of social media was a beneficial tool that provided increased communication opportunities, connections to communication partners, and networks of support. Specific results are discussed with reference to the research as well as implications for practice and recommendations for future research.ConclusionsAs individuals with ALS experience loss of function, some communication modes may no longer be viable. Providing access to different modes of communication, including social media, can allow independence, participation and better quality of life.

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Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Life Science Alliance ◽

10.26508/lsa.202000764 ◽

2021 ◽

Vol 4 (4) ◽

pp. e202000764

Author(s):

Arun Pal ◽

Benedikt Kretner ◽

Masin Abo-Rady ◽

Hannes Glaβ ◽

Banaja P Dash ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Loss Of Function ◽

Dna Double Strand Breaks ◽

Hexanucleotide Repeat ◽

Rna Foci ◽

Repeat Expansions ◽

Organelle Motility ◽

Trafficking Defects ◽

Induced Pluripotent ◽

Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

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A Natural History Comparison of SOD1-Mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

10.21203/rs.3.rs-603164/v2 ◽

2021 ◽

Author(s):

Lu Tang ◽

Johannes Dorst ◽

Lu Chen ◽

Xiaolu Liu ◽

Yan Ma ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Large Scale ◽

Age Of Onset ◽

Diagnostic Delay ◽

Chinese Patients ◽

Common Mutation ◽

Progression Rate ◽

Causative Gene ◽

Sod1 Mutant ◽

Lateral Sclerosis

Abstract Background: The gene coding the Cu/Zn superoxide dismutase ( SOD1 ) was the first-identified causative gene of amyotrophic lateral sclerosis (ALS), and the second most common genetic cause for ALS worldwide. The promising therapeutic approaches targeting SOD1 mutations are on the road. The purpose of the present study was to compare the mutational and clinical features of Chinese and German patients with ALS carrying mutations in SOD1 gene, which will facilitate the strategy and design of SOD1 -targeted trials.Methods: Demographic and clinical characteristics were collected from two longitudinal cohorts in China and Germany. Chinese and German patients carrying SOD1 mutations were compared with regard to mutational distribution, age of onset, site of onset, body mass index (BMI) at diagnosis, diagnostic delay, progression rate, and survival.Results: A total of 66 Chinese and 84 German patients with 69 distinct SOD1 mutations were identified. The most common mutation in both populations was p.His47Arg. It was found in 8 Chinese and 2 German patients and consistently showed a slow progression of disease in both countries. Across all mutations, Chinese patients showed a younger age of onset (43.9 vs 49.9 years, p=0.002), a higher proportion of young-onset cases (62.5% vs 30.7%, p<0.001) and a lower BMI at diagnosis (22.8 vs 26.0, p<0.001) compared to German patients. Although riluzole intake was less frequent in Chinese patients (28.3% vs 81.3%, p<0.001), no difference in survival between populations was observed (p=0.90). Across both cohorts, female patients had a longer diagnostic delay (15.0 vs 11.0 months, p=0.01) and a prolonged survival (248.0 vs 60.0 months, p=0.005) compared to male patients.Conclusions: Our data demonstrate the distinct mutational and clinical spectrums of SOD1 -mutant patients in Asian and European populations. Clinical phenotypes seem to be primarily influenced by mutation-specific, albeit not excluding ethnicity-specific factors. Further large-scale transethnical studies are needed to clarify determinants and modifiers of SOD1 phenotypes.

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Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106866 ◽

2020 ◽

pp. jmedgenet-2020-106866 ◽

Cited By ~ 2

Author(s):

Emily P McCann ◽

Lyndal Henden ◽

Jennifer A Fifita ◽

Katharine Y Zhang ◽

Natalie Grima ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Genetic Variation ◽

Genetic Analysis ◽

Genetic Variants ◽

Age Of Onset ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Whole Genome ◽

Identity By Descent ◽

Sporadic Als ◽

Lateral Sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.

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The motor neurone disorders

10.1093/med/9780198569381.003.0524 ◽

2011 ◽

Author(s):

Pamela Shaw

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Muscular Atrophy ◽

Motor Neurone ◽

System Control ◽

Loss Of Function ◽

The United Kingdom ◽

System Degeneration ◽

Motor Neurones ◽

Related Group ◽

Lateral Sclerosis

The motor neurone diseases are a group of disorders in which there is selective loss of function of upper and/or lower motor neurones in the motor cortex, brainstem, and spinal cord resulting in impairment in the nervous system control of voluntary movement. The term ‘motor neurone disease’, often abbreviated to ‘MND’, is used differently in different countries. In the United Kingdom it is used as an umbrella term to cover the related group of neurodegenerative disorders including amyotrophic lateral sclerosis, the commonest variant, as well as progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy. However, in many other countries amyotrophic lateral sclerosis, referred to as ALS, has been adopted as the umbrella term for this group of clinical variants of motor system degeneration. There is a tendency now internationally to use the ALS/MND abbreviation to cover this group of conditions. Careful diagnosis within the motor neurone diseases is essential for advising about prognosis, potential genetic implications, and for identifying those with acquired lower motor neurone syndromes who may benefit for the administration of immunomodulatory therapy.

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