TY - JOUR
T1 - Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons
AU - Klein, Christopher J.
AU - Wu, Yanhong
AU - Vogel, Peter
AU - Goebel, Hans H.
AU - Bönnemann, Carsten
AU - Zukosky, Kristen
AU - Botuyan, Maria Victoria
AU - Duan, Xiaohui
AU - Middha, Sumit
AU - Atkinson, Elizabeth J.
AU - Mer, Georges
AU - Dyck, Peter J.
PY - 2014/3/11
Y1 - 2014/3/11
N2 - Objective: To identify the genetic cause of axonal hereditary motor and sensory neuropathy (HMSN2) with infrequent giant axons. Methods: We studied 11 members of a previously described HMSN2 family with infrequent giant axons and variable cardiomyopathy. Whole-exome sequencing (WES) was performed on 2 affected persons and 1 unaffected person. Sanger sequencing was utilized to confirm the identified novel variant tracking with the affected status. Linkage analysis and haplotype mapping were obtained to confirm the causal nature of the identified variant. Cotransfection of HEK293 cells and co-immunoprecipitation assay were performed to assess the impact of the identified mutant protein in the implicated ubiquitin ligase pathway. Results: Giant axons with neurofilament accumulations were found in 3 affected persons who had undergone nerve biopsy evaluations. Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family. Linkage and haplotype analysis using microsatellite markers supported this variant as causal. The mutation is within the DCAF8 WD repeat region critical for its binding to DDB1. Functional analysis shows DCAF8 p.R317C reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function. Conclusions: Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy. This mutation results in decreased DDB1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation.
AB - Objective: To identify the genetic cause of axonal hereditary motor and sensory neuropathy (HMSN2) with infrequent giant axons. Methods: We studied 11 members of a previously described HMSN2 family with infrequent giant axons and variable cardiomyopathy. Whole-exome sequencing (WES) was performed on 2 affected persons and 1 unaffected person. Sanger sequencing was utilized to confirm the identified novel variant tracking with the affected status. Linkage analysis and haplotype mapping were obtained to confirm the causal nature of the identified variant. Cotransfection of HEK293 cells and co-immunoprecipitation assay were performed to assess the impact of the identified mutant protein in the implicated ubiquitin ligase pathway. Results: Giant axons with neurofilament accumulations were found in 3 affected persons who had undergone nerve biopsy evaluations. Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family. Linkage and haplotype analysis using microsatellite markers supported this variant as causal. The mutation is within the DCAF8 WD repeat region critical for its binding to DDB1. Functional analysis shows DCAF8 p.R317C reduces the association of DCAF8 and DDB1, which is important in Cul4-ubiquitin E3 function. Conclusions: Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy. This mutation results in decreased DDB1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation.
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U2 - 10.1212/WNL.0000000000000206
DO - 10.1212/WNL.0000000000000206
M3 - Article
C2 - 24500646
AN - SCOPUS:84898757440
SN - 0028-3878
VL - 82
SP - 873
EP - 878
JO - Neurology
JF - Neurology
IS - 10
ER -