X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C&gt;T substitution in the UBA1 gene

Jędrzejowska, Maria; Jakubowska-Pietkiewicz, Elżbieta; Kostera‐Pruszczyk, Anna

doi:10.1016/j.nmd.2015.05.001

Cited by 13 publications

(28 citation statements)

References 22 publications

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“…Specific links between UBA1 and neurodegenerative diseases affecting the human population have recently been established, with strong clinical and experimental data highlighting roles for UBA1 in SMA. Mutations in UBA1 cause a rare form of SMA known as X-linked SMA (XL-SMA), a disease that is clinically similar to SMA but not caused by homozygous deletion of the SMN1 gene [10,54,55] . Clinically, XL-SMA is characterized by muscle weakness associated with anterior horn motor neuron loss, hypotonia , and areflexia .…”

Section: Uba1 and The Regulation Of Neurodegenerationmentioning

confidence: 99%

“…Clinically, XL-SMA is characterized by muscle weakness associated with anterior horn motor neuron loss, hypotonia , and areflexia . Moreover, in contrast to SMA, XL-SMA is typically associated with congenital contractures and fractures [10,54,55] . Pathologically, widespread sensory and cerebellar abnormalities have been described, although the thalamic pathology that is often observed in SMN1 -dependent SMA was absent [54] .…”

Section: Uba1 and The Regulation Of Neurodegenerationmentioning

confidence: 99%

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UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

Groen

Gillingwater

2015

Trends in Molecular Medicine

114

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Neurodegenerative diseases are a leading cause of disability and early death. A common feature of these conditions is disruption of protein homeostasis. Ubiquitin-like modifier activating enzyme 1 (UBA1), the E1 ubiquitin-activating enzyme, sits at the apex of the ubiquitin cascade and represents an important regulator of cellular protein homeostasis. Critical contributions of UBA1-dependent pathways to the regulation of homeostasis and degeneration in the nervous system are emerging, including specific disruption of UBA1 in spinal muscular atrophy (SMA) and Huntington's disease (HD). In this review we discuss recent findings that put UBA1 at the centre of cellular homeostasis and neurodegeneration, highlighting the potential for UBA1 to act as a promising therapeutic target for a range of neurodegenerative diseases.

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Section: Uba1 and The Regulation Of Neurodegenerationmentioning

confidence: 99%

Section: Uba1 and The Regulation Of Neurodegenerationmentioning

confidence: 99%

UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

Groen

Gillingwater

2015

Trends in Molecular Medicine

114

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“…However, SMAX2 is characterized by facial dysmorphia, cryptorchidism, severe congenital contracture, and fractures. Most patients die of respiratory failure several months after birth (4,19). Baumbach et al recommended that the diagnosis of SMAX2 should be based on clinical performances, with congenital hypotonia and areflexia on physical examination, congenital contractures and/or fractures, contractures at birth, and the loss of anterior horn cells in the spinal cord and brain stem, normal SMN1 molecular sequencing, and male gender in a simple case or an X-linked manner of inheritance in families with multiple patients (18).…”

Section: Discussionmentioning

confidence: 99%

“…The incidence of SMAX2 is currently unknown. According to the National Center for Biotechnology Information (NCBI), the clinical and molecular studies of few SMAX2 families are reported so far (4,9,19,20). In Table 1, the clinical features and variant sites are reviewed in detail.…”

Section: Discussionmentioning

confidence: 99%

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A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)

et al. 2020

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Background: Infantile X-linked spinal muscular atrophy (SMAX2) is a rare type of spinal muscular atrophy associated with UBA1 variants.Methods: Clinical imaging and neurophysiological tests were performed on a Chinese patient with SMAX2. Further, focused panel sequencing of UBA1 was carried out on samples of both the proband and his maternal relatives.Results: The proband, a 4-year-old boy with the SMAX2 phenotype, suffered from reduced exercise capacity since infancy. His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability. The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions. Five male members of the proband's family were affected with the SMAX2 phenotype. They presented similar symptoms and had experienced a long and autonomous life. Molecular analysis revealed a novel missense variant (c.1617G>A, p.Met539Ile) in the exon 15 of UBA1. The proband's mother, as well as grandmother, carried the heterozygous missense UBA1 variant; whereas, the male patients from the family carried the hemizygotic variant. Conclusions:The affected members in this Chinese family showed unique features such as extended life span, no fractures, and cramps as compared with previously reported SMAX2 cases. The novel missense variant (c.1617G>A (p.Met539Ile) in UBA1 highlights the critical role of this gene in causing SMAX2 phenotype.

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A novel Xp11.22–22.33 deletion suggesting a possible mechanism of congenital cervical spinal muscular atrophy

Liu

Wang

et al. 2021

Molec Gen & Gen Med

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Background Congenital cervical spinal muscular atrophy (CCSMA) is a rare, nonprogressive, neurogenic disorder characterized by symmetric arthrogryposis and motor deficits mainly confined to upper extremities. Since its first proposal by Darwish et al. 39 years ago, only few cases have ever been reported. Vascular insult to the anterior horn of cervical spinal cord during fetal development was speculated to be the cause, however, the exact pathogenesis is still not well understood. Methods In this study, whole‐exome sequencing (WES) and copy number variation (CNV) analysis were conducted on a definitive CCSMA patient, confirmed by the clinical manifestations and other supplementary examinations. Results On physical examination, the patient was mainly characterized by symmetric, congenital, nonprogressive contractures, hypotonia, and muscle weakness mainly confined to the upper limbs, which were further supported by MRI and electromyography. Neuromuscular biopsy of the deltoid muscle demonstrated the type 1 myofiber predominance without any infiltration of inflammatory cells. The WES and CNV analysis unveiled a de novo Xp11.22–22.33 deletion. On further examination of the genes contained within this segment, we recognize UBA1 gene as the most likely pathogenic gene. Ubiquitin‐like modifier activating enzyme 1 is encoded by UBA1 gene (MIM 314370) located in Xp11.3 and is a critical protein that plays a vital role in ubiquitin‐proteasome system and autophagy. It is well documented that UBA1 gene mutation causes X‐linked infantile spinal muscular atrophy (XL‐SMA), which manifests phenotypes of arthrogryposis, hypotonia, and myopathic face. Type 2 XL‐SMA, which follows a nonprogressive and nonlethal course is very similar to the presentations of CCSMA. Conclusion The phenotypic similarities between this CCSMA case and XL‐SMA prompt us to hypothesize a possible connection between UBA1 gene deficit and the pathogenesis of CCSMA. Our study is the first to demonstrate that CCSMA might have a genetic etiology, thus, expanding our insights into the underlying cause of CCSMA.

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X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene

Cited by 13 publications

References 22 publications

UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)

A novel Xp11.22–22.33 deletion suggesting a possible mechanism of congenital cervical spinal muscular atrophy

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