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AFG3L2

Chr 18p11.21

AFG3 like matrix AAA peptidase subunit 2

Aliases:
SPAX5
MANE:
ENST00000269143.8
OMIM: 604581 ↗NCBI: 10939 ↗Ensembl ↗

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Predicted protein structure

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

  • Adult onset dystonia, chorea or related movement disorder

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • Adult onset neurodegenerative disorder

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • Ataxia and cerebellar anomalies - narrow panel

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • Childhood onset hereditary spastic paraplegia

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • DDG2P

    BIALLELIC, autosomal or pseudoautosomal

  • Early onset dystonia

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • Hereditary ataxia

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

  • Hereditary ataxia with onset in adulthood

    BOTH monoallelic and biallelic, autosomal or pseudoautosomal

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Disease associations (Open Targets)

  • spinocerebellar ataxia type 28

    0.84

  • spastic ataxia 5

    0.83

  • optic atrophy 12

    0.80

  • Early-onset spastic ataxia-neuropathy syndrome

    0.79

  • optic atrophy

    0.52

  • Dystonia

    0.45

  • AFG3L2-related optic atrophy and/or spastic ataxia spectrum

    0.37

  • Intellectual disability

    0.37

  • neurodegenerative disease

    0.35

  • spastic ataxia

    0.34

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

Mitochondrial inner membrane m-AAA protease component AFG3L2

Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development (PubMed:19748354, PubMed:28396416, PubMed:29932645, PubMed:30683687, PubMed:31327635, PubMed:37917749, PubMed:38157846, PubMed:41075794). AFG3L2 possesses both ATPase and protease activities: the ATPase activity is required to unfold substrates, threading them into the internal proteolytic cavity for hydrolysis into small peptide fragments (PubMed:19748354, PubMed:31327635). The m-AAA protease carries out quality control in the inner membrane of the mitochondria by mediating degradation of mistranslated or misfolded polypeptides (PubMed:26504172, PubMed:30683687, PubMed:34718584). The m-AAA protease complex also promotes the processing and maturation of mitochondrial proteins, such as MRPL32/bL32m, PINK1 and SP7 (PubMed:22354088, PubMed:29932645, PubMed:30252181). Mediates protein maturation of the mitochondrial ribosomal subunit MRPL32/bL32m by catalyzing the cleavage of the presequence of MRPL32/bL32m prior to assembly into the mitochondrial ribosome (PubMed:29932645). Required for SPG7 maturation into its active mature form after SPG7 cleavage by mitochondrial-processing peptidase (MPP) (PubMed:30252181). Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP) (PubMed:22354088). Acts as a regulator of calcium in neurons by mediating degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU (PubMed:27642048, PubMed:28396416). Promotes the proteolytic degradation of GHITM upon hyperpolarization of mitochondria: progressive GHITM degradation leads to respiratory complex I degradation and broad reshaping of the mitochondrial proteome by AFG3L2 (PubMed:35912435). Also acts as a regulator of mitochondrial glutathione homeostasis by mediating cleavage and degradation of SLC25A39 (PubMed:37917749, PubMed:38157846). SLC25A39 cleavage is prevented when SLC25A39 binds iron-sulfur (PubMed:37917749, PubMed:38157846). Also acts as a regulator of carnitine biosynthesis by mediating cleavage and degradation of SLC25A45 (PubMed:41075794). Involved in the regulation of OMA1-dependent processing of OPA1 (PubMed:17615298, PubMed:29545505, PubMed:30252181, PubMed:30683687, PubMed:32600459). May act by mediating processing of OMA1 precursor, participating in OMA1 maturation (PubMed:29545505)

Diseases associated with AFG3L2

Curated MONDO disease pages that list AFG3L2 among their top associated genes.

Data sources: HGNC (CC BY 4.0), AlphaFold (CC BY 4.0, Jumper et al. Nature 2021), Genomics England PanelApp (CC BY 4.0), ClinGen, Open Targets (CC0), UniProt.

Not for sole clinical decision-making. Always verify against primary sources.