Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy

被引：7

作者：

Cutrupi, Anthony N. ^{[1
,2
,12
]}

Narayanan, Ramesh K. ^{[1
,2
]}

Perez-Siles, Gonzalo ^{[1
,2
]}

Grosz, Bianca R. ^{[1
,2
]}

Lai, Kaitao ^{[1
,3
]}

Boyling, Alexandra ^{[1
,2
]}

Ellis, Melina ^{[1
,2
]}

Lin, Ruby C. Y. ^{[2
,4
]}

Neumann, Brent ^{[5
,6
]}

Mao, Di ^{[7
,8
]}

Uesugi, Motonari ^{[7
,8
]}

Nicholson, Garth A. ^{[1
,9
]}

Vucic, Steve ^{[2
,10
]}

Saporta, Mario A. ^{[11
]}

Kennerson, Marina L. ^{[1
,2
,9
]}

机构：

[1] ANZAC Res Inst, Northcott Neurosci Lab, Sydney, NSW 2139, Australia

[2] Univ Sydney, Fac Med & Hlth, Sydney, NSW 2006, Australia

[3] Univ Sydney, Fac Med & Hlth, Charles Perkins Ctr, Ancestry & Hlth Genom Lab, Sydney, NSW 2006, Australia

[4] Westmead Inst Med Res, Ctr Infect Dis & Microbiol, Sydney, NSW 2145, Australia

[5] Monash Univ, Monash Biomed Discovery Inst, Melbourne, Vic 3800, Australia

[6] Monash Univ, Dept Anat & Dev Biol, Melbourne, Vic 3800, Australia

[7] Kyoto Univ, Inst Integrated Cell Mat Sci, Uji 6110011, Japan

[8] Kyoto Univ, Inst Chem Res, Uji 6110011, Japan

[9] Concord Repatriat Gen Hosp, Mol Med Lab, Sydney, NSW 2139, Australia

[10] Concord Repatriat Gen Hosp, Brain & Nerve Res Ctr, Sydney, NSW 2139, Australia

[11] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA

[12] ANZAC Res Inst, Northcott Neurosci Lab, Concord Repatriat Gen Hosp, Gate 3 Hosp Rd, Sydney, NSW 2139, Australia

来源：

BRAIN | 2023年 / 146卷 / 03期

关键词：

iPSC-derived motor neurons; distal hereditary motor neuropathy; gene-intergenic fusion; ubiquitin E3 ligase; ubiquitin proteasome system; MARIE-TOOTH-DISEASE; SPINAL MUSCULAR-ATROPHY; STRUCTURAL VARIATION; GENOMIC REARRANGEMENTS; DOMINANT MUTATION; NEURON DISEASE; MECHANISMS; ALIGNMENT; DATABASE; DOMAIN;

D O I：

10.1093/brain/awac424

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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. Cutrupi et al. describe the formation of a novel gene-intergenic fusion involving the UBE3C gene in patients with distal hereditary motor neuropathy 1 (DHMN1). The transcript (UBE3C-IF) results in decreased UBE3C protein levels in hiPSC motor neurons and causes synaptic transmission deficits and susceptibility to heat stress in C. elegans.

引用

页码：880 / 897

页数：18