Alternative titles; symbols
HGNC Approved Gene Symbol: AFG3L2
SNOMEDCT: 715824008, 771469002;
Cytogenetic location: 18p11.21 Genomic coordinates (GRCh38) : 18:12,328,944-12,377,227 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p11.21 | Optic atrophy 12 | 618977 | Autosomal dominant | 3 |
| Spastic ataxia 5, autosomal recessive | 614487 | Autosomal recessive | 3 | |
| Spinocerebellar ataxia 28 | 610246 | Autosomal dominant | 3 |
AFG3L2 is the catalytic subunit of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (summary by Koppen et al., 2007). AFG3L2 also regulates the processing of OPA1 (605290) through OMA1 (617081), which ultimately affects mitochondrial dynamics (summary by Baderna et al., 2020).
By searching an EST database with the sequence of paraplegin (SPG7; 602783) and screening a fetal brain cDNA library, Banfi et al. (1999) identified a cDNA for AFG3L2. AFG3L2 encodes a deduced 797-amino acid protein whose sequence shows 69% similarity to the yeast Afg3 mitochondrial ATPase and 49% identity to paraplegin. AFG3L2 contains an AAA (for ATPase associated with diverse cellular activities) domain of about 190 amino acids with an ATP/GTP-binding site, a zinc-dependent binding domain, and an RNA-binding region. Northern blot analysis revealed that AFG3L2 is expressed ubiquitously as a 3.2-kb transcript in fetal and adult tissues, with greatest expression in heart and skeletal muscle. Fluorescence microscopy showed that AFG3L2 is localized in mitochondria. Thus, AFG3L2 and paraplegin share a similar expression pattern and the same localization.
Di Bella et al. (2010) noted that the AFG3L2 gene contains 17 exons spanning 48 kb.
By radiation hybrid analysis, Banfi et al. (1999) mapped the AFG3L2 gene to chromosome 18p11. Di Bella et al. (2010) noted that the AFG3L2 gene maps to chromosome 18p11.21.
Using in vitro protein binding assays and immunoprecipitation analysis, Koppen et al. (2007) showed that paraplegin interacted with AFG3L2 in the m-AAA protease complex. AFG3L2 also interacted with itself. Loss of paraplegin in Spg7 -/- mice or in SPG7 patient fibroblasts resulted in m-AAA protease complexes made up of only homodimerized AFG7L2 that were proteolytically active against misfolded mitochondrial membrane proteins in yeast complementation assays.
Di Bella et al. (2010) found expression of the AFG3L2 gene in Purkinje cell bodies and dendrites of the human cerebellum and in large neurons of the deep cerebellar layer. AFG3L2 and paraplegin were also expressed in pyramidal cortical neurons and spinal motor neurons. Similar expression was found in mouse tissues.
Konig et al. (2016) found that mouse Maip1 (617267) interacted with the m-AAA protease subunit Afg3l2 and comigrated with Afg3l1 (603020), Afg3l2, and Spg7 in an approximately 2.3-MDa complex. Knockout of AFG3L2, SPG7, or MAIP1 in HeLa cells significantly reduced levels of the precursor form of EMRE (SMDT1; 615588), an essential subunit of the mitochondrial calcium uniporter (MCU; 614197) complex. MAIP1 interacted directly with EMRE and appeared to protect the unassembled EMRE precursor from proteolytic degradation by YME1L1 (607472). In contrast, the m-AAA protease degraded unassembled EMRE in an MAIP1-independent manner and thus modulated formation of the approximately 400-kD MCU complexes. Loss of m-AAA protease activity disturbed neuronal MCU assembly in mouse neuronal mitochondria, deregulated mitochondrial Ca(2+) flux in HeLa cells, and rendered embryonic mouse neurons sensitive to mitochondrial permeability transition pore opening and MCU-dependent Ca(2+)-induced cell death.
In Afg3l2-null murine cells, Baderna et al. (2020) found that OPA1 was processed by OMA1 at a higher rate compared to wildtype, leading to a reduction in the long isoform of OPA1 (L-OPA1), which inhibited mitochondrial fusion and triggered mitochondrial network fragmentation.
Spinocerebellar Ataxia 28, Autosomal Dominant
In affected members of 5 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified 5 different heterozygous mutations in the AFG3L2 gene (604581.0001-604581.0005). Studies in yeast showed that the mutations affected respiratory and proteolytic functions of the protein by both dominant-negative (E691K; 604581.0001), and loss-of-function (see, e.g., S674L, 604581.0002) mechanisms. Di Bella et al. (2010) hypothesized that AFG3L2 or specific substrates of AFG3L2 may have an essential function in protecting the cerebellum from neurodegeneration.
Cagnoli et al. (2010) identified 6 different missense mutations in exons 15 and 16 of the AFG3L2 gene (see, e.g., 604581.0006-604581.0009) in 9 (2.6%) of 366 Caucasian European probands with autosomal dominant SCA who were negative for the most common triplet expansions in other genes. All mutations affected the highly conserved C-terminal peptidase-M41 domain and were predicted to destabilize the AFG3L2 complex. Pathogenic copy number variations affecting the AFG3L2 gene were not detected.
Spastic Ataxia 5, Autosomal Recessive
By whole-exome sequencing of 2 brothers with early-onset spastic ataxia-5 (SPAX5; 614487), Pierson et al. (2011) identified a homozygous mutation in the AFG3L2 gene (Y616C; 604581.0010). The phenotype was characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder.
In 2 unrelated Italian patients with a variant of SPAX5 presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous missense mutation in the AFG3L2 gene (M625I; 604581.0011). Functional studies of the variant were not performed. The patients were ascertained from a cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing.
In a 36-year-old woman (family 6) with SPAX5 and optic atrophy, Caporali et al. (2020) identified compound heterozygous missense mutations in the AFG3L2 gene (A462V, 604581.0014 and Q620K, 604581.0015). The mother and brother of this patient, who were heterozygous for the A462V mutation, had optic atrophy-12 (OPA12; 618977). The mutations were found by next-generation sequencing and confirmed by Sanger sequencing. The father of the proband was heterozygous for the Q620K variant; at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in abnormal OPA1 processing and mitochondrial fragmentation, consistent with a loss of function. The Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation.
In an 18-year-old man, born of unrelated parents (family 11), with SPAX5, Caporali et al. (2020) identified compound heterozygous mutations in the AFG3L2 gene (604581.0018 and 604581.0019). The mutations, which were found by next-generation sequencing, segregated with the disorder in the family. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected. Functional studies of these variants were not performed.
In an 8-year-old girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene (M625I, 604581.0011; c.245dup, 604581.0020). Fibroblasts from the patient showed reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. Activation of OMA1 was detected in patient cells, evidenced by reduced OMA and OPA1 protein content. To test if the OMA1-mediated integrated stress response (ISR) was mediated through DELE1, DELE1 was silenced in patient fibroblasts, which resulted in slowed growth and reduced phosphorylation of eIF2-alpha compared to controls.
Optic Atrophy 12, Autosomal Dominant
In a father and son with optic atrophy-12 (OPA12; 618977), Charif et al. (2015) identified a heterozygous missense mutation in the AFG3L2 gene (R468C; 604581.0012). The variant occurred at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation.
In a 19-year-old Italian man with OPA12, Colavito et al. (2017) identified a heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability.
In 5 affected individuals spanning 3 generations of a family with OPA12, Baderna et al. (2020) identified a heterozygous missense variant affecting a conserved residue close to the AAA domain in the AFG3L2 gene (G337E; 604581.0013). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the G337E mutation abolished AFG3L2 activity, resulting in a reduction of L-OPA1 and an accumulation of S-OPA1 associated with hyperactivation of OMA1. These abnormalities were associated with altered mitochondrial morphology and dynamics and increased mitochondrial fragmentation.
In affected individuals from 10 unrelated families with OPA12, Caporali et al. (2020) identified heterozygous missense mutations in the AFG3L2 gene (see, e.g., 604581.0014; 604581.0016-604581.0017). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The variants were inherited in an autosomal dominant pattern in most families, but occurred de novo in at least 2 patients. Most of the mutations localized to the ATPase domain, which is in contrast to SCA28 or SPAX5 mutations, which tend to affect the proteolytic domain. Functional studies were performed on several of the mutations. Expression of the mutations into yeast lacking the AFG3L2 orthologs showed that the mutant proteins were unable to rescue the defective oxidative phosphorylation (OXPHOS) phenotype. The mutations also impaired proteolytic and dislocase activity of the AFG3L2-associated mAAA complex, consistent with a loss of function. Patient fibroblasts showed decreased levels of L-OPA1 compared to S-OPA1, suggesting increased proteolytic cleavage of long OPA1 and abnormal accumulation of short OPA1. This was associated with increased mitochondrial fragmentation, although OXPHOS complex activity was normal in patient cells. The findings suggested that unbalanced processing of OPA1 due to AFG3L2 dysfunction causes defective mitochondrial dynamics, resulting in optic atrophy. The authors noted that this mechanism fits with the paradigm of the pathogenic mechanism for mitochondrial optic neuropathies, in which retinal ganglion cells are vulnerable to mitochondrial dysfunction.
Martinelli et al. (2009) reported an early-onset severe neurologic phenotype in Spg7-null/Afg3l2 +/- double-mutant mice characterized by loss of balance, tremor, and ataxia. Double-mutant mice displayed acceleration and worsening of the axonopathy observed in Spg7-null mice. In addition, they showed prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues were prone to lose mtDNA and had unstable respiratory complexes. At late stages, neurons contained structural abnormal mitochondria defective in COX-SDH reaction. Martinelli et al. (2009) suggested that different neuronal populations may have variable thresholds of susceptibility to reduced levels of the m-AAA protease and that impaired mitochondrial proteolysis may be a mechanism of cerebellar degeneration.
Franchino et al. (2024) identified reduced OMA1 expression in the cerebellum of Afg3l2 knockout mice (Afg3l2 -/-) compared to controls at postnatal day 14 (P14). There was evidence of activation of the mitochondrial integrated stress response (ISR), including increased phosphorylation of eIF2-alpha and increased ATF4 and FGF21 gene expression, among other genes associated with ISR. Franchino et al. (2024) then investigated the effects of treatment with an ISR potentiator, Sephin-1, on Afg3l2 -/- mice. Pregnant mothers were treated orally with Sephin-1 and Afg3l2 -/- pups were then treated intraperitoneally with Sephin-1 injections. The treated mutant mice had improved life span and motor performance compared to untreated mutant mice. Purkinje cells from brains from the treated mutant mice at P14 had improved mitochondrial appearance and basal ATP levels compared to untreated mutant mice. Franchino et al. (2024) concluded that activation of the OMA1-mediated ISR response is neuroprotective in Afg3l2 -/- mice.
In 11 affected members of an Italian family with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), reported by Cagnoli et al. (2006), Di Bella et al. (2010) identified a heterozygous 2071G-A transition in exon 16 of the AFG3L2 gene, resulting in a glu691-to-lys (E691K) substitution within the highly conserved proteolytic domain. One asymptomatic individual carried the mutation, which was not found in 400 controls. Molecular modeling showed that the E691K substitution affects a residue that sits in the middle of the central pore surrounding the exit from the proteolytic chamber on the matrix side of the complex. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. Coexpression with wildtype AFG3L2 or paraplegin (602783) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity.
In a father and son with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2-bp deletion/2-bp insertion (2021delCCinsTA) in exon 16 of the AFG3L2 gene, resulting in a ser674-to-leu (S674L) substitution in a portion of the proteolytic domain. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity.
In a man with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2081C-A transversion in exon 16 of the AFG3L2 gene, resulting in an ala694-to-glu (A694E) substitution in a portion of the proteolytic domain. His deceased father was also affected. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity.
In a 40-year-old woman with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 2105G-A transition in exon 16 of the AFG3L2 gene, resulting in an arg702-to-gln (R702Q) substitution in a portion of the proteolytic domain. The patient had onset at age 28 years of progressive gait and limb ataxia, with later development of dysarthria, ophthalmoplegia, and pyramidal signs. Brain MRI showed marked cerebellar atrophy. Two clinically unaffected family members in their seventies also carried the mutation; they both reported a subjective sense of unsteadiness and showed moderate cerebellar atrophy on brain MRI. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. The mechanism appeared to be loss of function and haploinsufficiency, since coexpression with either wildtype AFG3L2 or paraplegin (602783) restored respiration. Further studies showed that the mutant protein had impaired proteolytic activity.
In 6 affected members of a family with spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified a heterozygous 1296A-C transversion in exon 10 of the AFG3L2 gene, resulting in an asn432-to-thr (N432T) substitution within a highly conserved region of the ATPase domain. Molecular modeling showed that the N432T substitution occurs in a conserved residue in the central pore region on the membrane side of the channel through which substrates are translocated into the proteolytic chamber. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect at high temperatures. Coexpression with wildtype AFG3L2 or paraplegin (602783) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity.
In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1996A-G transition in exon 16 of the AFG3L2 gene, resulting in a met666-to-val (M666V) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes.
In 2 affected members a family with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1997T-G transversion in exon 16 of the AFG3L2 gene, resulting in a met666-to-arg (M666R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Met666 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes.
In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 2011G-A transition in exon 16 of the AFG3L2 gene, resulting in a gly671-to-arg (G671R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. Gly671 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes.
In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 1961C-T transition in exon 15 of the AFG3L2 gene, resulting in a thr654-to-ile (T654I) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. The mutation was not identified in 380 French or Italian control chromosomes.
In 2 brothers, born of consanguineous Hispanic parents from Colombia, with autosomal recessive spastic ataxia-5 (SPAX5; 614487), Pierson et al. (2011) identified a homozygous 1847G-A transition in the AFG3L2 gene, resulting in a tyr616-to-cys (Y616C) substitution in a highly conserved residue at the beginning of the proteolytic domain. The mutation was found by whole-exome sequencing. The older patient developed spastic gait at age 2 years and eventually lost the ability to ambulate independently, whereas the younger brother never acquired independent ambulation and died at age 13 years of pneumonia. Both developed progressive myoclonic epilepsy associated with generalized tonic-clonic seizures at age 8 years. This was followed by progressive dysarthria, dysphagia, motor degeneration, and lower extremity weakness with distal muscle atrophy. The older brother showed dysmetria, dysdiadochokinesia, ataxic dysarthria, ptosis, oculomotor apraxia, and dystonic movements. Cognition was normal. Brain MRI showed moderate cerebellar atrophy, and nerve conduction studies showed an axonal sensorimotor neuropathy of the lower extremities. Electron microscopy of skeletal muscle showed misplaced mitochondria associated with large lipid droplets, and there was decreased mtDNA copy number. Both parents were without neurologic complaints and had normal neurologic and ophthalmologic exams, although the mother had mild cerebellar atrophy on brain imaging. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin (SPG7; 602783) in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder.
In 2 unrelated Italian patients with a variant of autosomal recessive spastic ataxia-5 (SPAX5; 614487), presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous c.1875G-A transition in the AFG3L2 gene, resulting in a met625-to-ile (M625I) substitution at a conserved residue in the proteolytic domain. The mutation, which was found by exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant were not performed. Haplotype analysis suggested that the mutation was identical by descent, although the patients were not known to be related. The patients were ascertained from a larger cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing.
In a girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene: M625I and a 1-bp duplication (c.245dup; 604581.0020) predicted to result in a frameshift and premature termination (Asn82LysfsTer6). The mutations were identified by sequencing of a panel of nuclear genes associated with mitochondrial disease. Each parent was a carrier of one of the mutations. Fibroblasts from the patient demonstrated reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential.
In a father and son with optic atrophy-12 (OPA12; 618977), Charif et al. (2015) identified a heterozygous c.1402C-T transition in exon 11 of the AFG3L2 gene, resulting in an arg468-to-cys (R468C) substitution at a highly conserved residue in the AAA domain. Functional studies of the variant and studies of patient cells were not performed. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Neither patient had ataxia or spasticity, but both had mild to moderate intellectual disability, which may or may not have been related to the AFG3L2 mutation.
In a 19-year-old Italian man with OPA12, Colavito et al. (2017) identified heterozygosity for the R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, and intellectual disability.
In 5 affected individuals spanning 3 generations of a family with optic atrophy-12 (OPA12; 618977), Baderna et al. (2020) identified a heterozygous c.1010G-A transition (c.1010G-A, NM_006796.2) in exon 8 of the AFG3L2 gene, resulting in a gly337-to-glu (G337E) substitution at a conserved residue close to the AAA domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. Overexpression of G337E, unlike expression of wildtype AFG3L2, failed to rescue mitochondrial fragmentation defects in Afg3l2-null murine cells, indicating that the G337E mutation abolishes AFG3L2 activity. Patient fibroblasts showed abnormal mitochondrial morphology with increased fragmentation of the mitochondrial network, a reduction of L-OPA1 (605290), and an accumulation of S-OPA1 associated with hyperactivation of OMA1 (617081). The findings were consistent with a defect in mitochondrial dynamics.
In affected members of 2 unrelated multigenerational families (F1 and F2) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1385C-T transition (c.1385C-T, NM_006796.3) in the AFG3L2 gene, resulting in an ala462-to-val (A462V) substitution in the ATPase domain. A mother and son from another family (F6) with OPA12 were heterozygous for the A462V mutation; the 65-year-old mother also had cervical dystonia. Her daughter was compound heterozygous for A462V and a c.1858C-A transversion, resulting in a gln620-to-lys (Q620K; 604581.0015) substitution in the proteolytic domain. She had a more severe phenotype, consistent with autosomal recessive spastic ataxia-5 (SPAX5; 614487). The father of this patient was heterozygous for the Q620K variant: at age 64, he had no signs of OPA, but showed very mild ataxia on examination. In vitro functional expression studies showed that the A462V mutation resulted in a loss of function and caused mitochondrial fragmentation. Of note, the Q620K mutation resulted in less severe or even no defects compared to wildtype, consistent with the mild ataxic phenotype observed in 1 heterozygous carrier of this mutation.
For discussion of the c.1858C-A transversion (c.1858C-A, NM_006796.3) in the AFG3L2 gene, resulting in a gln620-to-lys (Q620K) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; 614487) by Caporali et al. (2020), see 604581.0014.
In a father and son (family 4) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1220A-G transition (c.1220A-G, NM_006796.3) in the AFG3L2 gene, resulting in an asp407-to-gly (D407G) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation.
In a father and son (family 5) with optic atrophy-12 (OPA12; 618977), Caporali et al. (2020) identified a heterozygous c.1541C-T transition (c.1541C-T, NM_006796.3) in the AFG3L2 gene, resulting in a pro514-to-leu (P514L) substitution in the ATPase domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused impaired AFG3L2 function, resulting in mitochondrial fragmentation.
In an 18-year-old man, born of unrelated parents (family 11), with autosomal recessive spastic ataxia-5 (SPAX5; 614487), Caporali et al. (2020) identified compound heterozygous mutations in the AFG3L2 gene: a 2-bp deletion (c.1901_1902delCT, NM_006796.3), resulting in a frameshift and premature termination (Ser634Ter), and a c.916A-G transition, resulting in a lys306-to-glu (K306E; 604581.0019) substitution. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the gnomAD database. Functional studies of the variants were not performed. In addition to cerebellar signs and dystonia, the patient had optic atrophy. The parents, who were each heterozygous for one of the mutations, were unaffected.
For discussion of the c.916A-G transition (c.916A-G, NM_006796.3) in the AFG3L2 gene, resulting in a lys306-to-glu (K306E) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic ataxia-5 (SPAX5; 614487) by Caporali et al. (2020), see 604581.0018.
For discussion of the 1-bp duplication (c.245dup) in the AFG3L2 gene, predicted to result in a frameshift and premature termination (Asn82LysfsTer6), that was identified in compound heterozygous state in a girl (patient 2) with spastic ataxia-5 (SPAX5; 614487) by Franchino et al. (2024), see 604581.0011.
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