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Human Genetics

, Volume 137, Issue 4, pp 329–342 | Cite as

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 Zhong Liu
  • Lingyun MeiEmail author
  • Yong FengEmail author
Original Investigation

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.

Notes

Acknowledgements

The authors would like to thank the family members for their invaluable cooperation and participation. The study was supported by a grant from the National Natural Science Foundation of China (Grants no. 81470705, 81771023, 81771024, 81500803), the Major State Basic Research Development Program of China (973 Program) (Grants no. 2014CB541702, 2014CB943003), National Institutes of Health/National Institute on Deafness and Other Communication Disorders (Grants no. R01 DC012115, R01 DC01246, R01 DC05575) and in part by the China Postdoctoral Science Foundation (Grants no. 2017M620359).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Patient consent

Obtained.

Ethical approval

The study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South university, in Hunan Province, China.

Data sharing

The raw data can be made available on reasonable request to researchers, after publication.

Supplementary material

439_2018_1885_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Wu Li
    • 1
    • 6
  • Jie Sun
    • 2
  • Jie Ling
    • 3
  • Jiada Li
    • 4
    • 5
  • Chufeng He
    • 1
    • 6
  • Yalan Liu
    • 1
    • 6
  • Hongsheng Chen
    • 1
    • 6
  • Meichao Men
    • 7
  • Zhijie Niu
    • 1
    • 6
  • Yuyuan Deng
    • 1
    • 6
  • Meng Li
    • 1
    • 6
  • Taoxi Li
    • 4
    • 5
  • Jie Wen
    • 1
    • 6
  • Shushan Sang
    • 1
    • 6
  • Haibo Li
    • 8
  • Zhengqing Wan
    • 4
    • 5
  • Elodie M. Richard
    • 9
  • Prem Chapagain
    • 10
    • 11
  • Denise Yan
    • 12
  • Xue Zhong Liu
    • 1
    • 12
    • 13
  • Lingyun Mei
    • 1
    • 6
    Email author
  • Yong Feng
    • 1
    • 6
    Email author
  1. 1.Department of Otolaryngology, Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Department of Otolaryngology, The Eight Affiliated HospitalSun Yat-sen UniversityShenzhenChina
  3. 3.Institute of Precision Medicine, Xiangya HospitalCentral South UniversityChangshaChina
  4. 4.Center for Medical GeneticsCentral South UniversityChangshaChina
  5. 5.School of Life SciencesCentral South University of ChinaChangshaChina
  6. 6.Province Key Laboratory of Otolaryngology Critical DiseasesChangshaChina
  7. 7.Health Management Center, Xiangya HospitalCentral South UniversityChangshaChina
  8. 8.Department of Ophthalmology, Xiangya HospitalCentral South UniversityChangshaChina
  9. 9.Department of Otorhinolaryngology Head and Neck Surgery, School of MedicineUniversity of MarylandBaltimoreUSA
  10. 10.Department of PhysicsFlorida International UniversityMiamiUSA
  11. 11.Biomolecular Sciences InstituteFlorida International UniversityMiamiUSA
  12. 12.Department of OtolaryngologyUniversity of Miami Miller School of MedicineMiamiUSA
  13. 13.Dr. John T. Macdonald Foundation, Department of Human GeneticsUniversity of Miami Miller School of MedicineMiamiUSA

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