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Cited by 124Mitochondrial Function and PathologyAutophagy in Disease and TherapyMetabolism and Genetic Disorders

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Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

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Hartmann, Bianca, Wai, Timothy, Hu, Hao, MacVicar, Thomas, Musante, Luciana, Fischer-Zirnsak, Björn, Stenzel, Werner, Gräf, Ralph, van den Heuvel, Lambert, Ropers, Hans-Hilger, Wienker, Thomas F, Hübner, Christoph, Langer, Thomas, Kaindl, Angela M·2016·eLife
DOI 10.7554/elife.16078PMC PMC4991934
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Abstract

Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.

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Figure 1. Phenotype and genotype of patients with YME1L1 mitochondriopathy. (A, B) The four affected patients are children of healthy, consanguineous parents of Saudi Arabian decent (□ male; ○ female; ◊ unknown gender; deceased; heterozygous, clinically not affected; ⚫/■ homozygous, affected; , consanguineous marriage). (C) Cranial MRIs reveal hyperintense changes (arrows) as a sign for leucencephalopathy, and cerebral atrophy (FLAIR, axial images). (D) Histological analysis of patient II.5 muscle biopsy specimen, from left to right: Gomori trichrome stain for muscle fibers revealed no conspicuous ragged red fibers indicative of a mitochondriopathy. Succinate dehydrogenase (SDH) and neuron specific enolase (NSE) staining revealed a neurogenic pattern with grouped fibers indicating denervation (magnification 200x). Electron microscopy (EM) revealed paracristalline inclusions (arrow) and altered cristae structure (“parking lots”, magnification 15,000x). (E) Whole exome sequencing discovered the homozygous mutation c.616C>T in exon 5 of the YME1L1 gene (NM_014263), localized at position 149 of the YME1L1 protein, and leading to an amino acid exchange of arginine to tryptophan in the mitochondrial targeting site (MTS; p.R149W, NP_055078). YME1L1 contains highly conserved domains: MTS, transmembrane domain (TM), ATPase domain (AAA+), motif of metalloprotease (Zinc) activity (HESGH). (F) Electropherogram depicting homozygous missense mutation in patient II.5, which is heterozygous in the father. (G) The mutation lies within a protein region, highly conserved throughout different species. (H) YME1L1 mRNA levels do not differ between patient and control primary human adult fibroblasts (Co, Control; II.5, patient II.5; ns, not significant; one-way ANOVA; p=0.2314; n=6 ) (I) Steady state levels of YME1L1 are below detection levels or profoundly reduced in cell lysates of patient II.5 YME1L1R149W; Yme1l1 knockout mouse fibroblasts serve as negative controls. YME1L1 protein levels in mitchondrial compartment fractions can be found Figure 1—figure supplement 1 (HAF, primary human adult fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient II.5; WT, wild type; KO, Yme1l1 knockout, n=5). DOI: http://dx.doi.org/10.7554/eLife.16078.002
Figure 1. Phenotype and genotype of patients with YME1L1 mitochondriopathy. (A, B) The four affected patients are children of healthy, consanguineous parents of Saudi Arabian decent (□ male; ○ female; ◊ unknown gender; deceased; heterozygous, clinically not affected; ⚫/■ homozygous, affected; , consanguineous marriage). (C) Cranial MRIs reveal hyperintense changes (arrows) as a sign for leucencephalopathy, and cerebral atrophy (FLAIR, axial images). (D) Histological analysis of patient II.5 muscle biopsy specimen, from left to right: Gomori trichrome stain for muscle fibers revealed no conspicuous ragged red fibers indicative of a mitochondriopathy. Succinate dehydrogenase (SDH) and neuron specific enolase (NSE) staining revealed a neurogenic pattern with grouped fibers indicating denervation (magnification 200x). Electron microscopy (EM) revealed paracristalline inclusions (arrow) and altered cristae structure (“parking lots”, magnification 15,000x). (E) Whole exome sequencing discovered the homozygous mutation c.616C>T in exon 5 of the YME1L1 gene (NM_014263), localized at position 149 of the YME1L1 protein, and leading to an amino acid exchange of arginine to tryptophan in the mitochondrial targeting site (MTS; p.R149W, NP_055078). YME1L1 contains highly conserved domains: MTS, transmembrane domain (TM), ATPase domain (AAA+), motif of metalloprotease (Zinc) activity (HESGH). (F) Electropherogram depicting homozygous missense mutation in patient II.5, which is heterozygous in the father. (G) The mutation lies within a protein region, highly conserved throughout different species. (H) YME1L1 mRNA levels do not differ between patient and control primary human adult fibroblasts (Co, Control; II.5, patient II.5; ns, not significant; one-way ANOVA; p=0.2314; n=6 ) (I) Steady state levels of YME1L1 are below detection levels or profoundly reduced in cell lysates of patient II.5 YME1L1R149W; Yme1l1 knockout mouse fibroblasts serve as negative controls. YME1L1 protein levels in mitchondrial compartment fractions can be found Figure 1—figure supplement 1 (HAF, primary human adult fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient II.5; WT, wild type; KO, Yme1l1 knockout, n=5). DOI: http://dx.doi.org/10.7554/eLife.16078.002CC BY · PubMed Central
Figure 1—figure supplement 1. (I) YME1L1R149W signal is barely detectable in total cell lysates (T), significantly reduced in the mitochondrial (M) but not present in the cytosolic (C) fraction of patient primary human adult fibroblasts (Co, Control; II.5, patient II.5; SDHA, succinate dehydrogenase; LDHA, lactate dehydrogenase; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.004
Figure 1—figure supplement 1. (I) YME1L1R149W signal is barely detectable in total cell lysates (T), significantly reduced in the mitochondrial (M) but not present in the cytosolic (C) fraction of patient primary human adult fibroblasts (Co, Control; II.5, patient II.5; SDHA, succinate dehydrogenase; LDHA, lactate dehydrogenase; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.004CC BY · PubMed Central
Figure 2. Mutation of arginine 149 impairs maturation of YME1L1 by MPP upon import into mitochondria. (A) YME1L1R149W is targeted to mitochondria. HeLa cells were transiently transfected with wild-type YME1L1, YME1L1R149W or the empty vector (EV) as control. Cells were analyzed by indirect immunofluorescence and co-localization of the immunofluorescent signals of antibodies against YME1L1 and ATP Synthase subunit beta (ATPase-ß) (WT, Wildtype; YME1L1-/-, Knockout; EV, empty vector; YME1L1R149W, patient mutation; Scale bar 10 µM). (B) Inhibition of the proteasome with MG132 (20 mM, 18 h) does not stabilize precursor or mature YME1L1 in Flp-In T-Rex HEK293T cells expressing YME1L1 or YME1L1 mutant variants: R149W, E381Q or R149W/E381Q. P4D1 antibodies were used as a control for ubiquitin accumulation and proteasome inhibition. (R149W, patient mutation; E381Q, dominant negative mutation of ATPase domain; R149W/E381Q, double mutant; *, unspecific signal; p, premature; m, mature; PoS, Ponceau staining; n=2). (C) Maturation of YME1L1 is mediated by mitochondrial processing peptidase (MPP) and impaired upon mutation of arginine 149. After site-directed mutagenesis of N-terminal arginine residues in YME1L1, the mutant proteins were expressed in a cell-free system and processing by recombinant MPP was examined (WT, wild type YME1L1; p, premature m, mature, n=2–3). (D) Cell-free MPP cleavage-assay: MPP can cleave YME1L1 but not YME1L1R149W from the premature to its mature form (min, minutes; p, premature; m, mature; YME1L1R149W, patient mutation; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.006
Figure 2. Mutation of arginine 149 impairs maturation of YME1L1 by MPP upon import into mitochondria. (A) YME1L1R149W is targeted to mitochondria. HeLa cells were transiently transfected with wild-type YME1L1, YME1L1R149W or the empty vector (EV) as control. Cells were analyzed by indirect immunofluorescence and co-localization of the immunofluorescent signals of antibodies against YME1L1 and ATP Synthase subunit beta (ATPase-ß) (WT, Wildtype; YME1L1-/-, Knockout; EV, empty vector; YME1L1R149W, patient mutation; Scale bar 10 µM). (B) Inhibition of the proteasome with MG132 (20 mM, 18 h) does not stabilize precursor or mature YME1L1 in Flp-In T-Rex HEK293T cells expressing YME1L1 or YME1L1 mutant variants: R149W, E381Q or R149W/E381Q. P4D1 antibodies were used as a control for ubiquitin accumulation and proteasome inhibition. (R149W, patient mutation; E381Q, dominant negative mutation of ATPase domain; R149W/E381Q, double mutant; *, unspecific signal; p, premature; m, mature; PoS, Ponceau staining; n=2). (C) Maturation of YME1L1 is mediated by mitochondrial processing peptidase (MPP) and impaired upon mutation of arginine 149. After site-directed mutagenesis of N-terminal arginine residues in YME1L1, the mutant proteins were expressed in a cell-free system and processing by recombinant MPP was examined (WT, wild type YME1L1; p, premature m, mature, n=2–3). (D) Cell-free MPP cleavage-assay: MPP can cleave YME1L1 but not YME1L1R149W from the premature to its mature form (min, minutes; p, premature; m, mature; YME1L1R149W, patient mutation; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.006CC BY · PubMed Central
Figure 3. Mutation of arginine 149 destabilizes YME1L1 but retains residual YME1L activity. (A) Stability of YME1L1 or YME1L1 mutant variants (R149W, E381Q and R149W/E381Q) expressed in Flp-In T-Rex HEK293T cells. The dominant negative E381Q mutation in the ATPase domain of YME1L1 prevents degradation of YME1L1R149W (E381Q, dominant negative mutation of ATPase domain; R149W, patient mutation; R149W/E381Q, double mutant; CHX, cycloheximide; h, hours; p, premature; m, mature; SDHA, succinate dehydrogenase; n=2). (B) Homozygous mutation in YME1L1 results in an accumulation of PRELID1 in the human patient. Yme1l1 knockout mouse fibroblasts serve as positive controls to demonstrate impaired proteolysis of PRELID1 (HAF, human adult primary fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient; WT, wild type; KO, knockout; n=5). (C) Mutation of arginine 149 of YME1L1 impairs processing of OPA1 with a decrease of short OPA1 form d levels. The formation of OPA1 form d indicates residual YME1L1 activity in human patient fibroblasts (immort. HAF, immortalized human adult fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient; WT, wild type; KO, knockout; n=6). The schematic diagram illustrates the proteolytic processing of OPA1 by YME1L1 on processing site 2 (S2) and OMA1 on processing site 1 (S1). The presence of long OPA1 forms (L-OPA1) is required for the maintenance of mitochondrial inner membrane fusion, whereas accumulation of short OPA1 forms (S-OPA1) is associated with accelerated fission. (D) Mitochondria-enriched membrane fractions from Flp-In T-Rex HEK293T cells expressing YME1L1 or YME1L1 mutant variants (R149W, E381Q and R149W/E381Q) were solubilized in digitonin and analyzed by sucrose gradient centrifugation. Fractions were collected and separated on SDS-PAGE for immunoblotting to detect high MW complexes of YME1L1. HSP60 complexes were used as a control (M, mitochondrial input, P, S, pellet and supernatant fraction after solubilization; HSP60, heat shock protein 60; E381Q, dominant negative mutation of ATPase domain; R149W, patient mutation; R149W/E381Q, double mutant). (E) Premature YME1L1/ YME1L1R149W is imported into the mitochondrial matrix via translocons of the outer mitochondrial membrane (TOMM) and inner mitochondrial membrane (TIMM). Here, MPP binds and cleaves the N-terminal mitochondrial targeting site (MTS) from premature YME1L1 but not YME1L1R149W, which then allows the mature and premature YME1L1R149W protein to assemble as proteolytic complex. DOI: http://dx.doi.org/10.7554/eLife.16078.007
Figure 3. Mutation of arginine 149 destabilizes YME1L1 but retains residual YME1L activity. (A) Stability of YME1L1 or YME1L1 mutant variants (R149W, E381Q and R149W/E381Q) expressed in Flp-In T-Rex HEK293T cells. The dominant negative E381Q mutation in the ATPase domain of YME1L1 prevents degradation of YME1L1R149W (E381Q, dominant negative mutation of ATPase domain; R149W, patient mutation; R149W/E381Q, double mutant; CHX, cycloheximide; h, hours; p, premature; m, mature; SDHA, succinate dehydrogenase; n=2). (B) Homozygous mutation in YME1L1 results in an accumulation of PRELID1 in the human patient. Yme1l1 knockout mouse fibroblasts serve as positive controls to demonstrate impaired proteolysis of PRELID1 (HAF, human adult primary fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient; WT, wild type; KO, knockout; n=5). (C) Mutation of arginine 149 of YME1L1 impairs processing of OPA1 with a decrease of short OPA1 form d levels. The formation of OPA1 form d indicates residual YME1L1 activity in human patient fibroblasts (immort. HAF, immortalized human adult fibroblasts; ACF, immortalized murine adult cardiac fibroblasts; MEF, immortalized murine embryonic fibroblast; Co, Control; II.5, patient; WT, wild type; KO, knockout; n=6). The schematic diagram illustrates the proteolytic processing of OPA1 by YME1L1 on processing site 2 (S2) and OMA1 on processing site 1 (S1). The presence of long OPA1 forms (L-OPA1) is required for the maintenance of mitochondrial inner membrane fusion, whereas accumulation of short OPA1 forms (S-OPA1) is associated with accelerated fission. (D) Mitochondria-enriched membrane fractions from Flp-In T-Rex HEK293T cells expressing YME1L1 or YME1L1 mutant variants (R149W, E381Q and R149W/E381Q) were solubilized in digitonin and analyzed by sucrose gradient centrifugation. Fractions were collected and separated on SDS-PAGE for immunoblotting to detect high MW complexes of YME1L1. HSP60 complexes were used as a control (M, mitochondrial input, P, S, pellet and supernatant fraction after solubilization; HSP60, heat shock protein 60; E381Q, dominant negative mutation of ATPase domain; R149W, patient mutation; R149W/E381Q, double mutant). (E) Premature YME1L1/ YME1L1R149W is imported into the mitochondrial matrix via translocons of the outer mitochondrial membrane (TOMM) and inner mitochondrial membrane (TIMM). Here, MPP binds and cleaves the N-terminal mitochondrial targeting site (MTS) from premature YME1L1 but not YME1L1R149W, which then allows the mature and premature YME1L1R149W protein to assemble as proteolytic complex. DOI: http://dx.doi.org/10.7554/eLife.16078.007CC BY · PubMed Central
Figure 4. YME1L1R149W causes mitochondrial fragmentation. (A, B) YME1L1R149W causes fragmentation (fragmentation or short tubules) of mitochondrial networks in patient fibroblasts (Co, Control, II.5, patient II.5; one-way ANOVA; n=150–200 cells; 4 replicates; scale bar 10 µm). (C) Co-transfection of mitochondrial GFP and human YME1L1/ YME1L1R149W protein in WT and Yme1l1-/- MEFs revealed that YME1L1 but not YME1L1R149Wcan rescue mitochondrial fragmentation in Yme1l1-/- MEFs and (D) increases the number of cells with tubular networks. Expression of YME1L1R149W partially rescues the fragmentation phenotype. In WT MEFs, YME1L1R149W expression results in only a mild, but not significant decline of cells with a tubular mitochondrial network (WT, wildtype; Yme1l1-/-, Yme1l1 Knockout; two-way ANOVA; n=3; scale bar 10 µm; **p<0.01; ***p<0.001; ****p<0.0001). DOI: http://dx.doi.org/10.7554/eLife.16078.008
Figure 4. YME1L1R149W causes mitochondrial fragmentation. (A, B) YME1L1R149W causes fragmentation (fragmentation or short tubules) of mitochondrial networks in patient fibroblasts (Co, Control, II.5, patient II.5; one-way ANOVA; n=150–200 cells; 4 replicates; scale bar 10 µm). (C) Co-transfection of mitochondrial GFP and human YME1L1/ YME1L1R149W protein in WT and Yme1l1-/- MEFs revealed that YME1L1 but not YME1L1R149Wcan rescue mitochondrial fragmentation in Yme1l1-/- MEFs and (D) increases the number of cells with tubular networks. Expression of YME1L1R149W partially rescues the fragmentation phenotype. In WT MEFs, YME1L1R149W expression results in only a mild, but not significant decline of cells with a tubular mitochondrial network (WT, wildtype; Yme1l1-/-, Yme1l1 Knockout; two-way ANOVA; n=3; scale bar 10 µm; **p<0.01; ***p<0.001; ****p<0.0001). DOI: http://dx.doi.org/10.7554/eLife.16078.008CC BY · PubMed Central
Figure 5. YME1L1 mutation impairs fibroblast cell growth and proliferation. (A) Significant reduction of cell culture growth (y-axis scale *104) and (B) proliferation of patient primary human adult fibroblasts after 120h under culture conditions (Co, Control; II.5, patient II.5; one-way ANOVA; ***p<0.001; ****p<0.0001; n=5 ). (C) No increase in apoptosis-sensitivity upon 2 µM staurosporine (STS) treatment in patient HAF after 6h (SDS-PAGE for cleaved PARP level (cPARP) (Co, Control; II.5, patient II.5; one-way ANOVA; p6h = 0.4283; n=3; ). (D) Normal respiratory chain subunit activity in patient HAF (U, units; mU, milli U; CS, Citrate synthase). (E) Cytochrome c oxidase subunit 4 (COX4) and NADH ubiquinone oxidoreductase 1 beta subcomplex 6 (NDUFB6) protein levels were not elevated in patient fibroblasts (Co, Control; II.5, patient II.5; n=3). (F) Decreased levels of mitochondrial compartment markers TOMM20 (translocon of outer mitochondrial membrane 20) for the outer membrane (OM), Cytochrome c for the intermembrane space (IMS), SDHA (succinate dehydrogenase) for the inner membrane (IM), and Cyclophilin D for the matrix in whole cell lysates of patient II.5 (Co, Control; II.5, patient II.5; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.015
Figure 5. YME1L1 mutation impairs fibroblast cell growth and proliferation. (A) Significant reduction of cell culture growth (y-axis scale *104) and (B) proliferation of patient primary human adult fibroblasts after 120h under culture conditions (Co, Control; II.5, patient II.5; one-way ANOVA; ***p<0.001; ****p<0.0001; n=5 ). (C) No increase in apoptosis-sensitivity upon 2 µM staurosporine (STS) treatment in patient HAF after 6h (SDS-PAGE for cleaved PARP level (cPARP) (Co, Control; II.5, patient II.5; one-way ANOVA; p6h = 0.4283; n=3; ). (D) Normal respiratory chain subunit activity in patient HAF (U, units; mU, milli U; CS, Citrate synthase). (E) Cytochrome c oxidase subunit 4 (COX4) and NADH ubiquinone oxidoreductase 1 beta subcomplex 6 (NDUFB6) protein levels were not elevated in patient fibroblasts (Co, Control; II.5, patient II.5; n=3). (F) Decreased levels of mitochondrial compartment markers TOMM20 (translocon of outer mitochondrial membrane 20) for the outer membrane (OM), Cytochrome c for the intermembrane space (IMS), SDHA (succinate dehydrogenase) for the inner membrane (IM), and Cyclophilin D for the matrix in whole cell lysates of patient II.5 (Co, Control; II.5, patient II.5; n=3). DOI: http://dx.doi.org/10.7554/eLife.16078.015CC BY · PubMed Central

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Authors
Hartmann, B., Wai, T., Hu, H., MacVicar, T., Musante, L., Fischer-Zirnsak, B., Stenzel, W., Gräf, R., van den Heuvel, L., Ropers, H.-H., Wienker, T. F., Hübner, C., Langer, T., & Kaindl, A. M.
Affiliations
  • Charité – Universitätsmedizin Berlin (DE)
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
  • Guangzhou Women and Children Medical Center (CN)
  • Max Planck Institute for Molecular Genetics (DE)
  • Max Planck Institute for Molecular Genetics, Berlin, Germany
  • University of Potsdam (DE)
  • Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, Netherlands
Corresponding author
Kaindl, Angela M
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2016-08-06
Volume
5
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.16078
PMC
PMC4991934
OpenAlex
W2480597918
Cited by
124
References
50
Citations by year
2026: 6 · 2025: 7 · 2024: 12 · 2023: 8 · 2022: 18 · 2021: 21 · 2020: 17 · 2019: 15 · 2018: 12 · 2017: 8
FWCI
6.07
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Max Planck Digital Library (submittedVersion, other-oa)
  • publish.UP (University of Potsdam) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
  • Sonnenfeld Stiftung
  • Deutsche Gesellschaft für Muskelkranke e.V.
  • Human Frontier Science Program
  • Max-Planck-Gesellschaft
  • Deutsche Forschungsgemeinschaft (KO2891/1-1, Reinhart Koselleck Grant, SFB665)
  • National Center for Research Resources (P20 RR016453)
  • EU FP 7 project GENCODYS (241995)
  • Berlin Institute of Health (BIH, CRG1)
  • Deutscher Akademischer Austauschdienst
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
optic atrophy, mitochondrial processing peptidase, mitochondrial presequence, consanguineous pedigree, missense mutations, protein degradation
MeSH terms
ATPases Associated with Diverse Cellular Activities, Female, Homozygote, Humans, Male, Metalloendopeptidases, Mitochondria, Optic Atrophy, Mutation, Missense, Mitochondrial Proteins, Mitochondrial Diseases

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