ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss

Wu Li, Jie Sun, Jie Ling, Jiada Li, Chufeng He, Yalan Liu, Hongsheng Chen, Meichao Men, Zhijie Niu, Yuyuan Deng, Meng Li, Taoxi Li, Jie Wen, Shushan Sang, Haibo Li, Zhengqing Wan, Elodie M. Richard, Prem Chapagain, Denise Yan, Xue Z LiuLingyun Mei, Yong Feng

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.

Original languageEnglish (US)
Pages (from-to)329-342
Number of pages14
JournalHuman Genetics
Volume137
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Genes
Hearing
Cell Movement
Exome
GTPase-Activating Proteins
Pedigree
Fluorescent Antibody Technique
Half-Life
Nonsyndromic Deafness
Exons
Western Blotting
Staining and Labeling
Phenotype
Mutation
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss. / Li, Wu; Sun, Jie; Ling, Jie; Li, Jiada; He, Chufeng; Liu, Yalan; Chen, Hongsheng; Men, Meichao; Niu, Zhijie; Deng, Yuyuan; Li, Meng; Li, Taoxi; Wen, Jie; Sang, Shushan; Li, Haibo; Wan, Zhengqing; Richard, Elodie M.; Chapagain, Prem; Yan, Denise; Liu, Xue Z; Mei, Lingyun; Feng, Yong.

In: Human Genetics, Vol. 137, No. 4, 01.04.2018, p. 329-342.

Research output: Contribution to journalArticle

Li, W, Sun, J, Ling, J, Li, J, He, C, Liu, Y, Chen, H, Men, M, Niu, Z, Deng, Y, Li, M, Li, T, Wen, J, Sang, S, Li, H, Wan, Z, Richard, EM, Chapagain, P, Yan, D, Liu, XZ, Mei, L & Feng, Y 2018, 'ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss', Human Genetics, vol. 137, no. 4, pp. 329-342. https://doi.org/10.1007/s00439-018-1885-0
Li, Wu ; Sun, Jie ; Ling, Jie ; Li, Jiada ; He, Chufeng ; Liu, Yalan ; Chen, Hongsheng ; Men, Meichao ; Niu, Zhijie ; Deng, Yuyuan ; Li, Meng ; Li, Taoxi ; Wen, Jie ; Sang, Shushan ; Li, Haibo ; Wan, Zhengqing ; Richard, Elodie M. ; Chapagain, Prem ; Yan, Denise ; Liu, Xue Z ; Mei, Lingyun ; Feng, Yong. / ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss. In: Human Genetics. 2018 ; Vol. 137, No. 4. pp. 329-342.
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abstract = "Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.",
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T1 - ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss

AU - Li, Wu

AU - Sun, Jie

AU - Ling, Jie

AU - Li, Jiada

AU - He, Chufeng

AU - Liu, Yalan

AU - Chen, Hongsheng

AU - Men, Meichao

AU - Niu, Zhijie

AU - Deng, Yuyuan

AU - Li, Meng

AU - Li, Taoxi

AU - Wen, Jie

AU - Sang, Shushan

AU - Li, Haibo

AU - Wan, Zhengqing

AU - Richard, Elodie M.

AU - Chapagain, Prem

AU - Yan, Denise

AU - Liu, Xue Z

AU - Mei, Lingyun

AU - Feng, Yong

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.

AB - Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.

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