Table 1.
Reported Disease-Causing Variants Associated with Defects in Mitochondrial Proteases
| Gene, Function (RefSeq#)a | Variant Effect on DNA and Protein Sequence (Linked SNPs) | Clinical Phenotype (OMIM#) | Evidence for Pathogenicity | Ref. |
|---|---|---|---|---|
| PMPCA, presequence cleavage (NM_015160.2) | 1. c.[1129G>A];[1129G>A],b p.[Ala377Thr];[Ala377Thr]; (rs753611141) 2. c.[287C>T];[1543G>A], p.[Ser96Leu];[Gly515Arg]; (rs869025292); (rs869025293) |
cerebellar ataxia (MIM: 213200) | Allelic frequency: 0%c p.Ala377Thr associated with deficient MPP activity in patient-derived cell lines; predicted to cause a catalytic activity or substrate binding defect p.Ser96Leu and p.Gly515Arg in structurally conserved domains |
Jobling et al.59 |
| PMPCB, presequence cleavage (NM_004279.2) | 1. c.[523C>T];[601G>C], p.[Arg175Cys];[Ala201Pro]; (rs145596167);(rs146343535) 2. c.[524G>A];[530T>G], p.[Arg175His];[Val177Gly]; (rs200188353); (rs1436866272) 3. c.[1265T>C];[1265T>C], p.[Ile422Thr];[Ile422Thr]; (rs1461200360) |
infantile neurodegeneration (MIM: 29576218) | p.Arg175Cys, p. Ala201Pro, and p.Ile422Thr decrease protein level and activity in fibroblast and/or hiPSCs/NESs patient cell lines, and severe growth and/or MPP processing defects in yeast complementation. p.Arg175His, p.Ala201Pro, p.Ile422Thr, and p.Val177Gly predicted to cause protein stability, active site, and/or dimerization defects |
Vögtle et al.57 |
| MIPEP,presequence trimming (NM_005932.3) | 1. c.[212T>A];[1745T>G], p.[Leu71Gln]; [Leu582Arg]; (rs10575118740); (rs1057518739) 2. c.[916C>T];[1804G>T], p.[Leu306Phe];[Glu602∗]; (rs143912947); (rs114638163) 3. c.[1027A>G];[1027A>G], p.[Lys343Glu];[Lys343Glu]; (rs1057518741) 4. c.[1534C>G]; + ch13: 1.4 Mb CNV_del, p.[His512Asp] |
left ventricular non-compaction (MIM: 602241) | Allelic frequency: 0%d for all variants except p.Leu306Phe = 8.2 × 10−6, p. pHis512Asp = 3.2 × 10−5 p.Leu71Gln and p.Lys343Glu and orthologous yeast mutants have decreased enzymatic activity p.Leu71Gln, p.Leu582Arg, p.Leu306Phe, p.Lys343Glu, and p.His512Asp predicted pathogenic |
Eldomery et al.105 |
| XPNPEP3, presequence trimming (NM_022098.3) | 1. c.[1357G>T]; [1357G>T], p.[Gly453Cys];[Gly453Cys]; (rs267607179)e 2. c.[931_934del];[931_934del], p.[Asn311Leufs∗5)];[(Asn311Leufs∗5]f |
nephronophthisis-like nephropathy-1 (MIM: 613159) | Allelic frequency: 0%g p.Gly453Cys has been showed to cause a splicing defect on patient’s mRNA | O’Toole et al.106 |
| PITRM1, post cleavage MTS degradation (NM_014889.3) | c.[548G>A];[548G>A], p.[Arg183Gln];[Arg183Gln]; (rs1249144069) | mental retardation, spinocerebellar ataxia, cognitive decline and psychosis | Allelic frequency: 0%h Protein instability, impaired cell proliferation, and mitochondrial function have been detected on patients’ fibroblasts and in vitro functional assay |
Brunetti et al.107 |
| HTRA2, intermembrane space protease (NM_013247.4) | 1. c.[1211G>A];[1211G>A], p.[Arg404Gln];[Arg404Gln]; (rs767006508) 2. c.[1316_1320del];[1316_1320del], p.[Ala439Aspfs∗15];[Ala439Aspfs∗15]; (rs1057519080) |
3-methylglutaronic aciduria type VIII, MGCA8 (MIM: 617248) | Allelic frequency: 0%3 Both variants cause complete absence of the protein; fibroblasts with p.Arg404Gln have impaired cell growth |
Mandel et al.108 |
| LONP1, matrix protease/chaperone (NM_004793.3) | 1. c.[2245C>T];[2300G>A], p.[Pro749Ser];[Gly767Glu]f 2. c.[1427A>C];[2245C>T], p.[Glu476Ala];[Pro749Ser] 3. c.[2009C>T];[2780_2782del], p.[Ala670Val];[Ile927del]f 4. c.[2014C>T];[2014C>T], p.[(Arg672Cys)];[(Arg672Cys)]f 5. c.[2009C>T];[2009C>T], p.[(Ala670Val)];[(Ala670Val)]f 6. c.[1392G>A]; [2036G>A], p.[(Trp464∗)f];[(Arg679His)]; (rs549574673) |
cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM:600373) | Allelic frequency: 0%c All variants except p.Arg679His predicted as pathogenic and to cause structural defects |
Dikoglu et al.109 |
| CLPP, matrix protease/chaperone (NM_006012.2) | 1. c.[433A>C];[433A>C], p.[Thr145Pro];[Thr145Pro]; (rs398123033) 2. c.[440G>C];[440G>C], p.[Cys147Ser];[Cys147Ser]; (rs398123034) 3. c.[270+4A>G];[270+4A>G]; (rs398123035) |
Perrault syndrome (MIM: 23541340) | Allelic frequency: 0%i p.Thr145Pro and p.Cys147Ser predicted as pathogenic and to cause folding defect c.270+4A>G caused splicing defect in vitro |
Jenkinson et al.110 |
| YME1L1, i-AAA-protease (NM_014263.3) | c.[445C>T];[445C>T], p.[Arg149Trp];[Arg149Trp]; (rs1057519312) | optic atrophy-11 (MIM: 617302) | Allelic frequency: 0%j Variant causes protein degradation, abnormal substrate processing, and other functional defects |
Hartmann et al.26 |
Abbreviations: hiPSC, human induced pluripotent stem cells; MPP, mitochondrial processing peptidase; NES, neuroepithelial stem cells.
a
All the identified DNA variants cosegregate with disease phenotype.
b
Founder mutation in a Lebanese Christian Maronite population.
c
Allelic frequency is based on control group from ExAC.
d
Allelic frequency is based on control groups from ExAC and Baylor-CMG exome.
e
Founder mutation in a Northern Finnish population.
f
dbSNP ID not applicable.
g
Allelic frequency is based on in-house control database, ethnicity or geographic-matched controls.
h
Allelic frequency is based on 1000 Genomes.
i
Allelic frequency is based on NHLBI Exome Sequencing Project (ESP) Exome Variant Server.
j
Allelic frequency is based on ExAC, 1000 Genomes, NHLBI Exome Sequencing Project (ESP) Exome Variant Server, dbSNP.