Table 2.
List of candidate genes implicated in mitochondrial dysfunction-associated POI
| GENES | VARIANTS | ACMG pathogenic classification | Domain | Knockout mice phenotype | References |
|---|---|---|---|---|---|
| RMND1 | c.713 A > G p. (Asn238Ser) | P | Domain of unknown function DUF155 226–403 | NR | [160] |
| c.583G > A p. (Gly195Arg) | VUS | Nondomain | [161] | ||
| c.818 A > C p. (Tyr273Ser) | LP | Domain of unknown function DUF155 226–403 | [161] | ||
| MRPS22 | c.605G > A p. (Arg202His) | LP | Small ribosomal subunit protein mS22 21–359 | Heterozygous MRPS22 knockout mice are fertile and show no overt abnormalities. Homozygous MRPS22 knockout results in embryonic lethality. | [124] |
| c.404G > A p. (Arg135Gln) | VUS | Small ribosomal subunit protein mS22 21–359 | [124] | ||
| POLG | c.2890 C > T p. (Arg964Cys) | VUS | Nondomain | premature aging and reduced lifespan. | [116, 162] |
| POLG2 | c.1297G > T p. (Asp433Tyr) | LP | Picornavirus capsid 359–522 | Heterozygous knockout mice are haplosufficient and develop normally; homozygous knockout mouse is embryonic lethal at day 8.0–8.5 p.c. with concomitant loss of mtDNA and mtDNA gene products. | [163, 164] |
| TFAM | c.694 C > T p. (Arg232Cys) | VUS | HMG-box_TFAM_rpt2 135–234 | Embryonic lethal, due to absence of mitochondrial DNA. Mutant embryos die before 10.5 dpc. | [119, 165] |
| LRPPRC | c.1061 C > T p. (Ala354Val) | P | Nondomain | Loss of hepatic LRPPRC results in growth delay, and pronounced liver histopathological abnormalities; Loss of LRPPRC induces defective respiration under phosphorylating conditions. | [166–168] |
| CLPB | c.1159 C > T p. (Arg387Ter) | P | AAA + ATPase domain 373–527 | NR | [129] |
| c.1257 + 5G > A p.? | LP | AAA + ATPase domain 373–527 | [129] | ||
| CLPP | c.628G > A p. (Ala210Thr) | VUS | CLP-protease 68–246 | Homozygous pups are born at about 60% of the expected Mendelian rate, indicating decreased intrauterine survival. Mutant mice are smaller in size than wild-type littermates, show decreased motor activity, are completely deaf after 12 months and their lifespan is decreased relative to that of wild-type littermates. Both female and male mutant mice are completely infertile due to defects in germ cell development. | [132, 169] |
| TWNK | c.1172G > A p. (Arg391His) | VUS | SF4 helicase domain 384–635 | NR | [47] |
| c.1754 A > G p. (Asn585Ser) | LP | SF4 helicase domain 384–635 | [47] | ||
| c.1519G > A p. (Val507Ile) | VUS | SF4 helicase domain 384–635 | [47] | ||
| c.1321T > G p. (Trp441Gly) | LP | SF4 helicase domain 384–635 | [47] | ||
| HARS2 | c.1010 A > G p. (Tyr337Cys) | VUS | Aminoacyl-tRNA synthetase, class II 62–417 | Disruption of Hars2in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice. | [48, 170] |
| LARS2 | c.1565 C > A p. (Thr522Asn) | LP | Aminoacyl-tRNA synthetase, class Ia 444–600 | NR | [48] |
| c.1077delT p.? | P | Nondomain | [48] | ||
| c.1886 C > T p. (Thr629Met) | VUS | Nondomain | [48] | ||
| TUFM | c.524G > C p. (Gly175Ala) | VUS | Translational (tr)-type GTP-binding domain 58–254 | NR | [171] |
| AARS2 | c.149T > G p. (Phe50Cys) | LP | Alanyl-tRNA synthetase, class IIc, core domain 37–792 | NR | [172] |
| c.1561 C > T p. (Arg521Ter) | P | Alanyl-tRNA synthetase, class IIc, core domain 37–792 | [172] |
Abbreviations: P, pathogenic; LP, likely pathogenic; VUS, variants of uncertain significance; LB: likely benign; B, benign; NR, no record