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Article ; Online: Identity-by-descent analysis of CMTX3 links three families through a common founder.

Henden, Lyndal / Grosz, Bianca R / Ellis, Melina / Nicholson, Garth A / Kennerson, Marina / Williams, Kelly L

2022

Abstract: A large 78 kb insertion from chromosome 8q24.3 into Xq27.1 was identified as the cause of CMTX3 in three families of European descent from Australia (CMT193, CMT180) and New Zealand/United Kingdom (CMT623). Using the relatedness tool XIBD to perform ... ...

Abstract	A large 78 kb insertion from chromosome 8q24.3 into Xq27.1 was identified as the cause of CMTX3 in three families of European descent from Australia (CMT193, CMT180) and New Zealand/United Kingdom (CMT623). Using the relatedness tool XIBD to perform genome-wide identity-by-descent (IBD) analysis on 16 affected individuals from the three families demonstrated they all share the CMTX3 disease locus identical-by-descent, confirming the mutation arose in a common ancestor. Relationship estimation from IBD segment data has genetically linked all three families through 6th and 7th degree relatives.
Language	English
Publishing date	2022-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1038/s10038-022-01078-1
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Zs.A 201: Show issues

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Article ; Online: Revisiting the pathogenic mechanism of the GJB1 5' UTR c.-103C > T mutation causing CMTX1.

Grosz, Bianca R / Svaren, John / Perez-Siles, Gonzalo / Nicholson, Garth A / Kennerson, Marina L

Neurogenetics

2021 Volume 22, Issue 3, Page(s) 149–160

Abstract: The second most common form of Charcot-Marie-Tooth neuropathy (CMT), X-linked CMT type X1 (CMTX1), is caused by coding and non-coding mutations in the gap junction beta 1 (GJB1) gene. The non-coding GJB1 c.-103C > T mutation (NM_000166.5) has been ... ...

Abstract	The second most common form of Charcot-Marie-Tooth neuropathy (CMT), X-linked CMT type X1 (CMTX1), is caused by coding and non-coding mutations in the gap junction beta 1 (GJB1) gene. The non-coding GJB1 c.-103C > T mutation (NM_000166.5) has been reported to cause CMTX1 in multiple families. This study assessed the internal ribosomal entry site (IRES) activity previously reported for the rat Gjb1 P2 5' untranslated region (UTR). Using a bicistronic assay and transfecting RT4 Schwann cells, IRES activity of the human GJB1 P2 5' UTR was compared to the GJB1 P2 5' UTR containing either the c.-103C > T mutation or the non-pathogenic c.-102G > A variant. No differences in GJB1 P2 5' UTR IRES activity were observed between the negative control, the wild-type P2 5' UTR, the c.-103C > T 5' UTR or the c.-102G > A 5' UTR, irrespective of the GJB1 intron being present (p = .429 with intron, and p = .865 without). A theoretical c.-131A > G variant was predicted to result in the same RNA secondary structure as the GJB1 c.-103C > T P2 5' UTR. However, no significant difference was observed between expression from the wild-type GJB1 P2 5' UTR and the GJB1 c.-131A > G variant (p = .688). Deletion of the conserved region surrounding the c.-103C > T mutation (c.-108_-103del) resulted in significantly higher expression than the c.-103C > T mutation alone (p = .019), suggesting that the conserved c.-108_-103 region was not essential for translation. The reporter assays in this study do not recapitulate the previously reported GJB1 IRES activity and suggest an alternate pathogenic mechanism for the c.-103C > T CMTX1 non-coding mutation.
MeSH term(s)	5' Untranslated Regions/drug effects ; Animals ; Charcot-Marie-Tooth Disease/etiology ; Charcot-Marie-Tooth Disease/genetics ; Connexins/genetics ; Gap Junctions/genetics ; Gap Junctions/pathology ; Genes, X-Linked/genetics ; Mutation/genetics ; Rats
Chemical Substances	5' Untranslated Regions ; Connexins
Language	English
Publishing date	2021-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1339887-8
ISSN	1364-6753 ; 1364-6745
ISSN (online)	1364-6753
ISSN	1364-6745
DOI	10.1007/s10048-021-00650-9
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Zs.A 5295: Show issues

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Article ; Online: Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.

Thumbadoo, Kyrah M / Dieriks, Birger V / Murray, Helen C / Swanson, Molly E V / Yoo, Ji Hun / Mehrabi, Nasim F / Turner, Clinton / Dragunow, Michael / Faull, Richard L M / Curtis, Maurice A / Siddique, Teepu / Shaw, Christopher E / Newell, Kathy L / Henden, Lyndal / Williams, Kelly L / Nicholson, Garth A / Scotter, Emma L

Brain : a journal of neurology

2024

Abstract: Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 ... ...

Abstract	Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases), and p.P497L (three cases)). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates, and p62, in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5), and UBQLN2-linked (n = 8) cases. We differentiate between i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis/and frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.
Language	English
Publishing date	2024-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awae140
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Article ; Online: Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.

Watchon, Maxinne / Robinson, Katherine J / Luu, Luan / An, Yousun / Yuan, Kristy C / Plenderleith, Stuart K / Cheng, Flora / Don, Emily K / Nicholson, Garth A / Lee, Albert / Laird, Angela S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 38, Issue 2, Page(s) e23429

Abstract: Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein ... ...

Abstract	Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent-insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB-treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in vitro and in vivo. While our results suggested that this activity may involve activity of a PKA/AMPK-dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.
MeSH term(s)	Humans ; Animals ; Butyric Acid/pharmacology ; Ataxin-3/genetics ; Machado-Joseph Disease/drug therapy ; Machado-Joseph Disease/genetics ; Zebrafish ; AMP-Activated Protein Kinases ; Neurodegenerative Diseases ; Protein Aggregates ; Proteomics ; Neuroblastoma ; Autophagy ; Animals, Genetically Modified ; Cyclic AMP-Dependent Protein Kinases
Chemical Substances	Butyric Acid (107-92-6) ; Ataxin-3 (EC 3.4.19.12) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Protein Aggregates ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202300963RR
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 296: Show issues

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Article ; Online: Structural variations causing inherited peripheral neuropathies: A paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation.

Cutrupi, Anthony N / Brewer, Megan H / Nicholson, Garth A / Kennerson, Marina L

Molecular genetics & genomic medicine

2018 Volume 6, Issue 3, Page(s) 422–433

Abstract: Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing ... ...

Abstract	Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot-Marie-Tooth neuropathy type 1A (CMT1A), is caused by a 1.5 Mb duplication causing trisomy of the dosage sensitive gene PMP22. Using genome sequencing, we recently identified two large genomic rearrangements causing IPN subtypes X-linked CMT (CMTX3) and distal hereditary motor neuropathy (DHMN1), thereby expanding the spectrum of SV mutations causing IPN. Understanding how newly discovered SVs can cause IPN may serve as a useful paradigm to examine the role of topologically associated domains (TADs), chromatin interactions, and gene dysregulation in disease. This review will describe the growing role of SV in the pathogenesis of IPN and the importance of considering this type of mutation in Mendelian diseases where protein coding mutations cannot be identified.
MeSH term(s)	Charcot-Marie-Tooth Disease/genetics ; Chromatin ; Chromosome Mapping ; Gene Dosage/genetics ; Genome ; Genomic Structural Variation/genetics ; Genomics ; Hereditary Sensory and Motor Neuropathy/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Peripheral Nervous System Diseases/genetics ; Peripheral Nervous System Diseases/physiopathology ; Point Mutation
Chemical Substances	Chromatin
Language	English
Publishing date	2018-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.390
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Article: The dominantly inherited motor and sensory neuropathies: clinical and molecular advances.

Nicholson, Garth A

Muscle & nerve

2006 Volume 33, Issue 5, Page(s) 589–597

Abstract: The rapid advances in the molecular genetics and cell biology of hereditary neuropathy have revealed great genetic complexity. It is a challenge for physicians and laboratories to keep pace with new discoveries. Classification of hereditary neuropathies ... ...

Abstract	The rapid advances in the molecular genetics and cell biology of hereditary neuropathy have revealed great genetic complexity. It is a challenge for physicians and laboratories to keep pace with new discoveries. Classification of hereditary neuropathies has evolved from a simple clinical to a detailed molecular classification. However, the molecular classification is not simple to use, as different mutations of the same gene produce a range of phenotypes. The logistics of testing for multiple gene mutations are considerable. This review gives a clinical overview of molecular and clinical advances in the dominant hereditary motor and sensory neuropathies [HMSNs, Charcot-Marie-Tooth (CMT) neuropathy], which account for some 60%-70% of families with CMT. The dominant forms of CMT have cellular mechanisms different from those of recessive forms and are a separate diagnostic challenge, so they are not included in this review. Diagnostic testing requires accurate clinical information and a selective approach to gene screening until the cost of multiple gene mutation screening falls. Accurate molecular diagnosis is critical to genetic counseling. This review concentrates on how molecular information can be used clinically, on how physicians can keep pace with new developments, and on the relevance of this new knowledge to patients.
MeSH term(s)	Animals ; Charcot-Marie-Tooth Disease/classification ; Charcot-Marie-Tooth Disease/genetics ; Genes, Dominant ; Hereditary Sensory and Motor Neuropathy/classification ; Hereditary Sensory and Motor Neuropathy/genetics ; Hereditary Sensory and Motor Neuropathy/therapy ; Humans ; Mutation ; Phenotype
Language	English
Publishing date	2006-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	438353-9
ISSN	1097-4598 ; 0148-639X
ISSN (online)	1097-4598
ISSN	0148-639X
DOI	10.1002/mus.20477
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Zs.A 1449: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 551: Show issues

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Article ; Online: Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Nementzik, Laura R / Thumbadoo, Kyrah M / Murray, Helen C / Gordon, David / Yang, Shu / Blair, Ian P / Turner, Clinton / Faull, Richard L M / Curtis, Maurice A / McLean, Catriona / Nicholson, Garth A / Swanson, Molly E V / Scotter, Emma L

Brain pathology (Zurich, Switzerland)

2023 Volume 34, Issue 3, Page(s) e13230

Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the ...

Abstract	Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and 8 non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.
MeSH term(s)	Humans ; Adaptor Proteins, Signal Transducing/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy-Related Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Mutation ; Transcription Factors/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; DNA-Binding Proteins ; Transcription Factors ; UBQLN2 protein, human ; TARDBP protein, human
Language	English
Publishing date	2023-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.13230
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Zs.A 3585: Show issues

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Article ; Online: Long read sequencing overcomes challenges in the diagnosis of SORD neuropathy.

Grosz, Bianca R / Stevanovski, Igor / Negri, Sara / Ellis, Melina / Barnes, Stephanie / Reddel, Stephen / Vucic, Steve / Nicholson, Garth A / Cortese, Andrea / Kumar, Kishore R / Deveson, Ira W / Kennerson, Marina L

Journal of the peripheral nervous system : JPNS

2022 Volume 27, Issue 2, Page(s) 120–126

Abstract: Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot-Marie-Tooth neuropathy (CMT2). We aimed to assess a novel long-read sequencing approach to overcome current limitations in ... ...

Abstract	Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot-Marie-Tooth neuropathy (CMT2). We aimed to assess a novel long-read sequencing approach to overcome current limitations in SORD neuropathy diagnostics due to the SORD2P pseudogene and the phasing of biallelic mutations in recessive disease. We conducted a screen of our Australian whole exome sequencing (WES) CMT cohort to identify individuals with homozygous or compound heterozygous SORD variants. Individuals detected with SORD mutations then underwent long-read sequencing, clinical assessment, and serum sorbitol analysis. An individual was detected with compound heterozygous truncating mutations in SORD exon 7, NM_003104.5:c.625C>T (p.Arg209Ter) and NM_003104.5:c.757del (p.Ala253GlnfsTer27). Subsequent Oxford Nanopore Tech (ONT) long-read sequencing was used to successfully differentiate SORD from the highly homologous non-functional SORD2P pseudogene and confirmed that the mutations were biallelic through haplotype-resolved analysis. The patient presented with axonal sensorimotor polyneuropathy (CMT2) and ulnar neuropathy without compression at the elbow. Burning neuropathic pain in the forearms and feet was also reported and was exacerbated by alcohol consumption and improved with alcohol cessation. UPLC-tandem mass spectrometry confirmed that the patient had elevated serum sorbitol levels (12.0 mg/L) consistent with levels previously observed in patients with biallelic SORD mutations. This represents a novel clinical presentation and expands the phenotype associated with biallelic SORD mutations causing CMT2. Our study is the first report of long-read sequencing for an individual with CMT and demonstrates the utility of this approach for clinical genomics.
MeSH term(s)	Australia ; Charcot-Marie-Tooth Disease/diagnosis ; Charcot-Marie-Tooth Disease/genetics ; Humans ; L-Iditol 2-Dehydrogenase/genetics ; Mutation ; Pedigree ; Phenotype ; Sorbitol ; Whole Exome Sequencing
Chemical Substances	Sorbitol (506T60A25R) ; L-Iditol 2-Dehydrogenase (EC 1.1.1.14)
Language	English
Publishing date	2022-03-05
Publishing country	United States
Document type	Case Reports ; Research Support, Non-U.S. Gov't
ZDB-ID	1364009-4
ISSN	1529-8027 ; 1085-9489
ISSN (online)	1529-8027
ISSN	1085-9489
DOI	10.1111/jns.12485
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Zs.A 5106: Show issues

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Article ; Online: A novel MCM3AP mutation in a Lebanese family with recessive Charcot-Marie-Tooth neuropathy.

Kennerson, Marina L / Corbett, Alastair C / Ellis, Melina / Perez-Siles, Gonzalo / Nicholson, Garth A

Brain : a journal of neurology

2018 Volume 141, Issue 9, Page(s) e66

MeSH term(s)	Acetyltransferases ; Charcot-Marie-Tooth Disease ; Humans ; Intellectual Disability ; Intracellular Signaling Peptides and Proteins ; Mutation
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Acetyltransferases (EC 2.3.1.-) ; MCM3AP protein, human (EC 2.3.1.-)
Language	English
Publishing date	2018-07-05
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awy184
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Article ; Online: Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy.

Cutrupi, Anthony N / Narayanan, Ramesh K / Perez-Siles, Gonzalo / Grosz, Bianca R / Lai, Kaitao / Boyling, Alexandra / Ellis, Melina / Lin, Ruby C Y / Neumann, Brent / Mao, Di / Uesugi, Motonari / Nicholson, Garth A / Vucic, Steve / Saporta, Mario A / Kennerson, Marina L

Brain : a journal of neurology

2022 Volume 146, Issue 3, Page(s) 880–897

Abstract: Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in ...

Abstract	Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.
MeSH term(s)	Animals ; Muscular Atrophy, Spinal/genetics ; Mutation ; Ubiquitin/genetics ; Ubiquitin-Protein Ligases/genetics ; Humans
Chemical Substances	Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; UBE3C protein, human (EC 2.3.2.26)
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awac424
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