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Genome Med. 2016 Nov 1;8(1):106.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
2
Institute of Biochemistry and Molecular Biology, ZBMZ and BIOSS Centre for Biological Signalling Studies and Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany.
3
Texas Children's Hospital, Houston, TX, 77030, USA.
4
Department of Pediatrics, Tawam Hospital, Al Ain, 15258, United Arab Emirates.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
6
Department of Pediatrics, University of Mississippi Medical Center, 2500N State St, Jackson, MS, 39216, USA.
7
Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX, 77030, USA.
8
Medical Genetics Center, Jiang Men Maternity and Childhealth Care Hospital, Jiang Men, 529000, China.
9
Huffington Center on Aging, Baylor College of Medicine, Houston, TX, 77030, USA.
10
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
11
Radboud Center for Mitochondrial Medicine, Department of Pediatrics, RadboudUMC, 6500HB, Nijmegen, Netherlands.
12
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
13
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. vrsutton@texaschildrens.org.
14
Texas Children's Hospital, Houston, TX, 77030, USA. vrsutton@texaschildrens.org.

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.

PMID:
27799064
PMCID:
PMC5088683
DOI:
10.1186/s13073-016-0360-6
[Indexed for MEDLINE]
Free PMC Article

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