TY - JOUR
T1 - MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
AU - Eldomery, Mohammad K.
AU - Akdemir, Zeynep C.
AU - Vögtle, F. Nora
AU - Charng, Wu Lin
AU - Mulica, Patrycja
AU - Rosenfeld, Jill A.
AU - Gambin, Tomasz
AU - Gu, Shen
AU - Burrage, Lindsay C.
AU - Al Shamsi, Aisha
AU - Penney, Samantha
AU - Jhangiani, Shalini N.
AU - Zimmerman, Holly H.
AU - Muzny, Donna M.
AU - Wang, Xia
AU - Tang, Jia
AU - Medikonda, Ravi
AU - Ramachandran, Prasanna V.
AU - Wong, Lee Jun
AU - Boerwinkle, Eric
AU - Gibbs, Richard A.
AU - Eng, Christine M.
AU - Lalani, Seema R.
AU - Hertecant, Jozef
AU - Rodenburg, Richard J.
AU - Abdul-Rahman, Omar A.
AU - Yang, Yaping
AU - Xia, Fan
AU - Wang, Meng C.
AU - Lupski, James R.
AU - Meisinger, Chris
AU - Sutton, V. Reid
N1 - Funding Information:
CM was supported by the Deutsche Forschungsgemeinschaft (DFG) and FNV by the Baden-Württemberg Stiftung and the Emmy-Noether-Program (DFG). W-LC is supported by CPRIT training program RP140102. This work was supported in part by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics (BH-CMG). LCB was supported by NIH T32 GM07526.
Funding Information:
We thank the family members, clinicians, Nijmegen Center for Mitochondrial Disorders (NCMD) and Dr Grazia Isaya, MD, PhD from Mayo clinic for their assistance and advice in this study. We thank Dr Chris Grant for Prx1 antiserum. CM was supported by the Deutsche Forschungsgemeinschaft (DFG) and FNV by the Baden-Wurttemberg Stiftung and the Emmy-Noether-Program (DFG). WLC is supported by CPRIT training program RP140102. This work was supported in part by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics (BH-CMG). LCB was supported by NIH T32 GM07526.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Background: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Methods: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Results: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. Conclusions: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.
AB - Background: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Methods: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Results: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. Conclusions: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.
UR - http://www.scopus.com/inward/record.url?scp=84994501908&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994501908&partnerID=8YFLogxK
U2 - 10.1186/s13073-016-0360-6
DO - 10.1186/s13073-016-0360-6
M3 - Article
C2 - 27799064
AN - SCOPUS:84994501908
SN - 1756-994X
VL - 8
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 106
ER -