title: A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.
abstract: OBJECTIVE
  To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern.
  
  
  METHODS
  We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation.
  
  
  RESULTS
  We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R(31_50del). The proteasomal inhibitor treatment increased the intracellular amount of σ1R(31_50del) and led to the formation of nuclear aggregates. Stable expressing σ1R(31_50del) induced endoplasmic reticulum stress and enhanced apoptosis.
  
  
  CONCLUSIONS
  The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN.
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Hu
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Xie
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zi
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wu
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China.
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
authors.affiliation: From the Department of Neurology, the Third Xiangya Hospital (X.L., L.L., Y.X., X.Z., R.Z.), State Key Laboratory of Medical Genetics (Z.H., J.W., K.X., B.T.), and Department of Physiology, Xiangya School of Medicine (X.L., L.W.), Central South University, Changsha, PR China. zhangruxu@vip.163.com.
authors.forename: Ruxu
authors.initials: R
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D044466:Asian People / Q000235:genetics; D002648:Child; D002681:China; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D005190:Family; D005260:Female; D005808:Genes, Recessive; D057809:HEK293 Cells; D006225:Hand / Q000473:pathology; D006801:Humans; D007866:Leg / Q000473:pathology; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D022821:RNA Splice Sites; D017480:Receptors, sigma / Q000235:genetics*; D000097605:Sigma-1 Receptor
chemical_list: D022821:RNA Splice Sites; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor