Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

Abstract

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex

“…2 H). TRIM47 is an E3 ubiquitin-protein ligase that mediates the degradation of CYLD lysine 63 deubiquitinase (CYLD) [ 76 ], which has very recently been highlighted as a rare causative gene for FTD [ 77 , 78 ] and possibly ALS [ 79 ]. Interestingly, CYLD is known to interact with proteins already implicated in ALS/FTD, such as TBK1, OPTN and SQSTM1 [ 77 ].…”

“…Interestingly, CYLD is known to interact with proteins already implicated in ALS/FTD, such as TBK1, OPTN and SQSTM1 [ 77 ]. Few cases have been described and there is debate around what effect the disease-associated mutations have on CYLD activity [ 79 , 80 ], however it is interesting to note that the most upregulated protein in the ALS frontal cortex is known to regulate levels of a protein directly implicated in FTD. Supporting the link between TRIM47 and cognitive change, TRIM47 was increased more than twofold in the ALSci samples.…”

CYLD variants identified in Alzheimer's disease and frontotemporal dementia patients

“…1). 20 All these rare CYLD variants were verified by Sanger sequencing. These variants exhibited extremely low frequency (minor allele frequency < 0.001) in the Genome Aggregation Database (gnomAD) database and were predicted to be damaging using the MutationTaster (https://www.mutationtaster.org/).…”

Synaptic proteomics reveal distinct molecular signatures of cognitive change andC9ORF72repeat expansion in the human ALS cortex

“…In the frontal cortex, TRIM47 was specifically upregulated more than 2-fold compared to control synapses (Figure 2H). TRIM47 is an E3 ubiquitin-protein ligase that mediates the degradation of CYLD lysine 63 deubiquitinase (CYLD) [71], which has very recently been highlighted as a rare causative gene for FTD [72, 73] and possibly ALS [74]. Interestingly, CYLD is known to interact with proteins already implicated in ALS/FTD, such as TBK1, OPTN and SQSTM1 [72].…”

“…Interestingly, CYLD is known to interact with proteins already implicated in ALS/FTD, such as TBK1, OPTN and SQSTM1 [72]. Few cases have been described and there is debate around what effect the disease-associated mutations have on CYLD activity [74, 75], however it is interesting to note that the most upregulated protein in the ALS frontal cortex is known to regulate levels of a protein directly implicated in FTD. Supporting the link between TRIM47 and cognitive change, TRIM47 was increased more than 2-fold in the ALSci samples.…”