A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.
OBJECTIVE
Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.


METHODS
We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family.


RESULTS
We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells.


CONCLUSIONS
Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.
Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Keqiang
K
Zhang
Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Jia-Wei
JW
Lin
Solexa Core Lab, Department of Molecular Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Jinhui
J
Wang
Division of Information Sciences, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Xiwei
X
Wu
Solexa Core Lab, Department of Molecular Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Hanlin
H
Gao
PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yi-Chen
YC
Hsieh
Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Peter
P
Hwu
Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
Yun-Ru
YR
Liu
Division of Information Sciences, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Leila
L
Su
School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
Hung-Yi
HY
Chiou
Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Daidong
D
Wang
Division of Information Sciences, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Yate-Ching
YC
Yuan
Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan.
Jacqueline
J
Whang-Peng
Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan.
Wen-Ta
WT
Chiu
1] Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA [2] PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yun
Y
Yen
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D055785:Gene Knockdown Techniques; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009442:Neurilemmoma / Q000235:genetics*; D017253:Neurofibromatoses / Q000235:genetics*; D010375:Pedigree; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071796:SMARCB1 Protein; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000235:genetics* / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C032165:ubiquinone 6; D014451:Ubiquinone; C024989:coenzyme Q10