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Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1

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Abstract

We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14–2q14 Jalili syndrome locus. The initial assessment and collection of the family were performed before the clinical delineation of Jalili syndrome. Another assessment was made after the discovery of the responsible gene and the dental abnormalities characteristic of Jalili syndrome were retrospectively identified. The p.R605X mutation represents the first probable founder mutation of Jalili syndrome identified in the Amish community. The molecular mechanism underlying Jalili syndrome is unknown. Here we show that CNNM4 interacts with IQCB1, which causes Leber congenital amaurosis (LCA) when mutated. A truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. Mutation p.R605X may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis, or both. Our data, for the first time, functionally link Jalili syndrome gene CNNM4 to LCA gene IQCB1, providing important insights into the molecular pathogenic mechanism of retinal dystrophy in Jalili syndrome.

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Abbreviations

WES:

Whole exome sequencing

CNNM4 :

Cyclin and CBS domain divalent metal cation transport mediator 4

LCA:

Leber congenital amaurosis

XSQ:

eXtensible SeQuence

MAF:

Minor allele frequency

SNVs:

Single-nucleotide variants

CNMP:

Cyclic nucleotide-monophosphate

AI:

Amelogenesis imperfect

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Acknowledgements

We thank all family members and study subjects for their support of the research and the members of Wang laboratory for help and technical assistance. We thank Dr. Hiroaki Miki for providing plasmid pCMV-Tag4A-CNNM4-WT, and Dr. William Y. Tsang for plasmid pCBF-IQCB1.

Funding

This study was supported by the China National Natural Science Foundation grants (91439129, 31430047), 2016 Top-Notch Innovative Talent Development Project from the Bureau of Human Resources and Social Security of Wuhan City, NIH/NHLBI grants R01 HL121358 and R01 HL126729, Hubei Province Natural Science Key Program (2014CFA074), the Chinese National Basic Research Programs (973 Programs 2013CB531101 and 2012CB517801), Hubei Province’s Outstanding Medical Academic Leader Program, Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education, and the “Innovative Development of New Drugs” Key Scientific Project (2011ZX09307-001-09); and by an unrestricted grant from Research to Prevent Blindness (EIT).

Author information

Author notes

  1. Sisi Li, Quansheng Xi, Xiaoyu Zhang, Dong Yu and Lin Li contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research and Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, 430074, China

    Sisi Li, Xiaoyu Zhang, Dong Yu, Zhenyang Jiang & Qing K. Wang

  2. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA

    Quansheng Xi, Lin Li, Qiuyun Chen & Qing K. Wang

  3. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, USA

    Qiuyun Chen & Qing K. Wang

  4. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  5. Center for Genetic Eye Diseases, Cleveland Clinic Cole Eye Institute, Cleveland, OH, 44195, USA

    Elias I. Traboulsi

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  1. Sisi Li
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  4. Dong Yu
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  5. Lin Li
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  6. Zhenyang Jiang
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  7. Qiuyun Chen
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  8. Qing K. Wang
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  9. Elias I. Traboulsi
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Corresponding authors

Correspondence to Qing K. Wang or Elias I. Traboulsi.

Ethics declarations

This study was approved by appropriate local institutional review boards on human subject research and conformed to the guidelines set forth by the Declaration of Helsinki.

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the IRB on human subject research at Cleveland Clinic and the Ethics Committee on human subject research at Huazhong University of Science and Technology and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all the study subjects.

Additional information

Communicated by S. Hohmann.

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Li, S., Xi, Q., Zhang, X. et al. Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1. Mol Genet Genomics 293, 699–710 (2018). https://doi.org/10.1007/s00438-018-1417-6

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  • DOI: https://doi.org/10.1007/s00438-018-1417-6

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