MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

Mohammad K. Eldomery, Zeynep C. Akdemir, F. Nora Vögtle, Wu Lin Charng, Patrycja Mulica, Jill A. Rosenfeld, Tomasz Gambin, Shen Gu, Lindsay C. Burrage, Aisha Al Shamsi, Samantha Penney, Shalini N. Jhangiani, Holly H Zimmerman, Donna M. Muzny, Xia Wang, Jia Tang, Ravi Medikonda, Prasanna V. Ramachandran, Lee Jun Wong, Eric Boerwinkle & 12 others Richard A. Gibbs, Christine M. Eng, Seema R. Lalani, Jozef Hertecant, Richard J. Rodenburg, Omar A. Abdul-Rahman, Yaping Yang, Fan Xia, Meng C. Wang, James R. Lupski, Chris Meisinger, V. Reid Sutton

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number106
JournalGenome Medicine
Volume8
Issue number1
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Muscle Hypotonia
Nucleotides
Peptide Hydrolases
Seizures
Yeasts
Exome
Saccharomyces cerevisiae Proteins
Comparative Genomic Hybridization
Genetic Association Studies
Cataract
Saccharomyces cerevisiae
Mitochondria
Mothers
Amino Acids
Mutation
Growth
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Eldomery, M. K., Akdemir, Z. C., Vögtle, F. N., Charng, W. L., Mulica, P., Rosenfeld, J. A., ... Sutton, V. R. (2016). MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. Genome Medicine, 8(1), [106]. https://doi.org/10.1186/s13073-016-0360-6

MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. / Eldomery, Mohammad K.; Akdemir, Zeynep C.; Vögtle, F. Nora; Charng, Wu Lin; Mulica, Patrycja; Rosenfeld, Jill A.; Gambin, Tomasz; Gu, Shen; Burrage, Lindsay C.; Al Shamsi, Aisha; Penney, Samantha; Jhangiani, Shalini N.; Zimmerman, Holly H; Muzny, Donna M.; Wang, Xia; Tang, Jia; Medikonda, Ravi; Ramachandran, Prasanna V.; Wong, Lee Jun; Boerwinkle, Eric; Gibbs, Richard A.; Eng, Christine M.; Lalani, Seema R.; Hertecant, Jozef; Rodenburg, Richard J.; Abdul-Rahman, Omar A.; Yang, Yaping; Xia, Fan; Wang, Meng C.; Lupski, James R.; Meisinger, Chris; Sutton, V. Reid.

In: Genome Medicine, Vol. 8, No. 1, 106, 01.11.2016.

Research output: Contribution to journalArticle

Eldomery, MK, Akdemir, ZC, Vögtle, FN, Charng, WL, Mulica, P, Rosenfeld, JA, Gambin, T, Gu, S, Burrage, LC, Al Shamsi, A, Penney, S, Jhangiani, SN, Zimmerman, HH, Muzny, DM, Wang, X, Tang, J, Medikonda, R, Ramachandran, PV, Wong, LJ, Boerwinkle, E, Gibbs, RA, Eng, CM, Lalani, SR, Hertecant, J, Rodenburg, RJ, Abdul-Rahman, OA, Yang, Y, Xia, F, Wang, MC, Lupski, JR, Meisinger, C & Sutton, VR 2016, 'MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death', Genome Medicine, vol. 8, no. 1, 106. https://doi.org/10.1186/s13073-016-0360-6
Eldomery, Mohammad K. ; Akdemir, Zeynep C. ; Vögtle, F. Nora ; Charng, Wu Lin ; Mulica, Patrycja ; Rosenfeld, Jill A. ; Gambin, Tomasz ; Gu, Shen ; Burrage, Lindsay C. ; Al Shamsi, Aisha ; Penney, Samantha ; Jhangiani, Shalini N. ; Zimmerman, Holly H ; Muzny, Donna M. ; Wang, Xia ; Tang, Jia ; Medikonda, Ravi ; Ramachandran, Prasanna V. ; Wong, Lee Jun ; Boerwinkle, Eric ; Gibbs, Richard A. ; Eng, Christine M. ; Lalani, Seema R. ; Hertecant, Jozef ; Rodenburg, Richard J. ; Abdul-Rahman, Omar A. ; Yang, Yaping ; Xia, Fan ; Wang, Meng C. ; Lupski, James R. ; Meisinger, Chris ; Sutton, V. Reid. / MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. In: Genome Medicine. 2016 ; Vol. 8, No. 1.
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abstract = "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.",
author = "Eldomery, {Mohammad K.} and Akdemir, {Zeynep C.} and V{\"o}gtle, {F. Nora} and Charng, {Wu Lin} and Patrycja Mulica and Rosenfeld, {Jill A.} and Tomasz Gambin and Shen Gu and Burrage, {Lindsay C.} and {Al Shamsi}, Aisha and Samantha Penney and Jhangiani, {Shalini N.} and Zimmerman, {Holly H} and Muzny, {Donna M.} and Xia Wang and Jia Tang and Ravi Medikonda and Ramachandran, {Prasanna V.} and Wong, {Lee Jun} and Eric Boerwinkle and Gibbs, {Richard A.} and Eng, {Christine M.} and Lalani, {Seema R.} and Jozef Hertecant and Rodenburg, {Richard J.} and Abdul-Rahman, {Omar A.} and Yaping Yang and Fan Xia and Wang, {Meng C.} and Lupski, {James R.} and Chris Meisinger and Sutton, {V. Reid}",
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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

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.

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