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

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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Eldomery, Mohammad K. [verfasserIn] 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

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	Respiratory Chain Complex Whole Exome Sequencing Oct1 Protein Whole Exome Sequencing Data Oct1 Activity

Anmerkung:	© The Author(s). 2016

Übergeordnetes Werk:	Enthalten in: Genome medicine - London : BioMed Central, 2009, 8(2016), 1 vom: 01. Nov.
Übergeordnetes Werk:	volume:8 ; year:2016 ; number:1 ; day:01 ; month:11

Links:	Volltext

DOI / URN:	10.1186/s13073-016-0360-6

Katalog-ID:	SPR030646863

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100	1		\|a Eldomery, Mohammad K. \|e verfasserin \|4 aut
245	1	0	\|a MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
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520			\|a 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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allfields	10.1186/s13073-016-0360-6 doi (DE-627)SPR030646863 (SPR)s13073-016-0360-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2016 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. Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213 Akdemir, Zeynep C. aut Vögtle, F.-Nora aut Charng, Wu-Lin aut Mulica, Patrycja aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Gu, Shen aut Burrage, Lindsay C. aut Al Shamsi, Aisha aut Penney, Samantha aut Jhangiani, Shalini N. aut Zimmerman, Holly H. aut Muzny, Donna M. aut Wang, Xia aut Tang, Jia aut Medikonda, Ravi aut Ramachandran, Prasanna V. aut Wong, Lee-Jun aut Boerwinkle, Eric aut Gibbs, Richard A. aut Eng, Christine M. aut Lalani, Seema R. aut Hertecant, Jozef aut Rodenburg, Richard J. aut Abdul-Rahman, Omar A. aut Yang, Yaping aut Xia, Fan aut Wang, Meng C. aut Lupski, James R. aut Meisinger, Chris aut Sutton, V. Reid aut Enthalten in Genome medicine London : BioMed Central, 2009 8(2016), 1 vom: 01. Nov. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:8 year:2016 number:1 day:01 month:11 https://dx.doi.org/10.1186/s13073-016-0360-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2016 1 01 11
spelling	10.1186/s13073-016-0360-6 doi (DE-627)SPR030646863 (SPR)s13073-016-0360-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2016 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. Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213 Akdemir, Zeynep C. aut Vögtle, F.-Nora aut Charng, Wu-Lin aut Mulica, Patrycja aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Gu, Shen aut Burrage, Lindsay C. aut Al Shamsi, Aisha aut Penney, Samantha aut Jhangiani, Shalini N. aut Zimmerman, Holly H. aut Muzny, Donna M. aut Wang, Xia aut Tang, Jia aut Medikonda, Ravi aut Ramachandran, Prasanna V. aut Wong, Lee-Jun aut Boerwinkle, Eric aut Gibbs, Richard A. aut Eng, Christine M. aut Lalani, Seema R. aut Hertecant, Jozef aut Rodenburg, Richard J. aut Abdul-Rahman, Omar A. aut Yang, Yaping aut Xia, Fan aut Wang, Meng C. aut Lupski, James R. aut Meisinger, Chris aut Sutton, V. Reid aut Enthalten in Genome medicine London : BioMed Central, 2009 8(2016), 1 vom: 01. Nov. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:8 year:2016 number:1 day:01 month:11 https://dx.doi.org/10.1186/s13073-016-0360-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2016 1 01 11
allfields_unstemmed	10.1186/s13073-016-0360-6 doi (DE-627)SPR030646863 (SPR)s13073-016-0360-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2016 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. Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213 Akdemir, Zeynep C. aut Vögtle, F.-Nora aut Charng, Wu-Lin aut Mulica, Patrycja aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Gu, Shen aut Burrage, Lindsay C. aut Al Shamsi, Aisha aut Penney, Samantha aut Jhangiani, Shalini N. aut Zimmerman, Holly H. aut Muzny, Donna M. aut Wang, Xia aut Tang, Jia aut Medikonda, Ravi aut Ramachandran, Prasanna V. aut Wong, Lee-Jun aut Boerwinkle, Eric aut Gibbs, Richard A. aut Eng, Christine M. aut Lalani, Seema R. aut Hertecant, Jozef aut Rodenburg, Richard J. aut Abdul-Rahman, Omar A. aut Yang, Yaping aut Xia, Fan aut Wang, Meng C. aut Lupski, James R. aut Meisinger, Chris aut Sutton, V. Reid aut Enthalten in Genome medicine London : BioMed Central, 2009 8(2016), 1 vom: 01. Nov. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:8 year:2016 number:1 day:01 month:11 https://dx.doi.org/10.1186/s13073-016-0360-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2016 1 01 11
allfieldsGer	10.1186/s13073-016-0360-6 doi (DE-627)SPR030646863 (SPR)s13073-016-0360-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2016 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. Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213 Akdemir, Zeynep C. aut Vögtle, F.-Nora aut Charng, Wu-Lin aut Mulica, Patrycja aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Gu, Shen aut Burrage, Lindsay C. aut Al Shamsi, Aisha aut Penney, Samantha aut Jhangiani, Shalini N. aut Zimmerman, Holly H. aut Muzny, Donna M. aut Wang, Xia aut Tang, Jia aut Medikonda, Ravi aut Ramachandran, Prasanna V. aut Wong, Lee-Jun aut Boerwinkle, Eric aut Gibbs, Richard A. aut Eng, Christine M. aut Lalani, Seema R. aut Hertecant, Jozef aut Rodenburg, Richard J. aut Abdul-Rahman, Omar A. aut Yang, Yaping aut Xia, Fan aut Wang, Meng C. aut Lupski, James R. aut Meisinger, Chris aut Sutton, V. Reid aut Enthalten in Genome medicine London : BioMed Central, 2009 8(2016), 1 vom: 01. Nov. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:8 year:2016 number:1 day:01 month:11 https://dx.doi.org/10.1186/s13073-016-0360-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2016 1 01 11
allfieldsSound	10.1186/s13073-016-0360-6 doi (DE-627)SPR030646863 (SPR)s13073-016-0360-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2016 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. Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213 Akdemir, Zeynep C. aut Vögtle, F.-Nora aut Charng, Wu-Lin aut Mulica, Patrycja aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Gu, Shen aut Burrage, Lindsay C. aut Al Shamsi, Aisha aut Penney, Samantha aut Jhangiani, Shalini N. aut Zimmerman, Holly H. aut Muzny, Donna M. aut Wang, Xia aut Tang, Jia aut Medikonda, Ravi aut Ramachandran, Prasanna V. aut Wong, Lee-Jun aut Boerwinkle, Eric aut Gibbs, Richard A. aut Eng, Christine M. aut Lalani, Seema R. aut Hertecant, Jozef aut Rodenburg, Richard J. aut Abdul-Rahman, Omar A. aut Yang, Yaping aut Xia, Fan aut Wang, Meng C. aut Lupski, James R. aut Meisinger, Chris aut Sutton, V. Reid aut Enthalten in Genome medicine London : BioMed Central, 2009 8(2016), 1 vom: 01. Nov. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:8 year:2016 number:1 day:01 month:11 https://dx.doi.org/10.1186/s13073-016-0360-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2016 1 01 11
language	English
source	Enthalten in Genome medicine 8(2016), 1 vom: 01. Nov. volume:8 year:2016 number:1 day:01 month:11
sourceStr	Enthalten in Genome medicine 8(2016), 1 vom: 01. Nov. volume:8 year:2016 number:1 day:01 month:11
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Respiratory Chain Complex Whole Exome Sequencing Oct1 Protein Whole Exome Sequencing Data Oct1 Activity
isfreeaccess_bool	true
container_title	Genome medicine
authorswithroles_txt_mv	Eldomery, Mohammad K. @@aut@@ Akdemir, Zeynep C. @@aut@@ Vögtle, F.-Nora @@aut@@ Charng, Wu-Lin @@aut@@ Mulica, Patrycja @@aut@@ Rosenfeld, Jill A. @@aut@@ Gambin, Tomasz @@aut@@ Gu, Shen @@aut@@ Burrage, Lindsay C. @@aut@@ Al Shamsi, Aisha @@aut@@ Penney, Samantha @@aut@@ Jhangiani, Shalini N. @@aut@@ Zimmerman, Holly H. @@aut@@ Muzny, Donna M. @@aut@@ Wang, Xia @@aut@@ Tang, Jia @@aut@@ Medikonda, Ravi @@aut@@ Ramachandran, Prasanna V. @@aut@@ Wong, Lee-Jun @@aut@@ Boerwinkle, Eric @@aut@@ Gibbs, Richard A. @@aut@@ Eng, Christine M. @@aut@@ Lalani, Seema R. @@aut@@ Hertecant, Jozef @@aut@@ Rodenburg, Richard J. @@aut@@ Abdul-Rahman, Omar A. @@aut@@ Yang, Yaping @@aut@@ Xia, Fan @@aut@@ Wang, Meng C. @@aut@@ Lupski, James R. @@aut@@ Meisinger, Chris @@aut@@ Sutton, V. Reid @@aut@@
publishDateDaySort_date	2016-11-01T00:00:00Z
hierarchy_top_id	594424275
id	SPR030646863
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR030646863</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520010404.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2016 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-016-0360-6</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030646863</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13073-016-0360-6-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Eldomery, Mohammad K.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s). 2016</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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. 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author	Eldomery, Mohammad K.
spellingShingle	Eldomery, Mohammad K. misc Respiratory Chain Complex misc Whole Exome Sequencing misc Oct1 Protein misc Whole Exome Sequencing Data misc Oct1 Activity MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
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topic_title	MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death Respiratory Chain Complex (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Oct1 Protein (dpeaa)DE-He213 Whole Exome Sequencing Data (dpeaa)DE-He213 Oct1 Activity (dpeaa)DE-He213
topic	misc Respiratory Chain Complex misc Whole Exome Sequencing misc Oct1 Protein misc Whole Exome Sequencing Data misc Oct1 Activity
topic_unstemmed	misc Respiratory Chain Complex misc Whole Exome Sequencing misc Oct1 Protein misc Whole Exome Sequencing Data misc Oct1 Activity
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title	MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
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title_full	MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
author_sort	Eldomery, Mohammad K.
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author_browse	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
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title_sort	mipep recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
title_auth	MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
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. © The Author(s). 2016
abstractGer	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. © The Author(s). 2016
abstract_unstemmed	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. © The Author(s). 2016
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title_short	MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR030646863</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520010404.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2016 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-016-0360-6</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030646863</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13073-016-0360-6-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Eldomery, Mohammad K.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s). 2016</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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. 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MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

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