AFG3L2 – Spinocerebellar Ataxia Type 28

Autosomal dominant spinocerebellar ataxia type 28 (SCA28) is a progressive neurodegenerative disorder characterized by gait and limb ataxia, dysarthria, nystagmus, slow saccades, and hyperreflexia. SCA28 is caused by heterozygous mutations in the mitochondrial m-AAA protease subunit AFG3L2, which impair proteolytic function and mitochondrial quality control ([PMID:20208537]).

Genetic studies demonstrate autosomal dominant inheritance with multiple independent pedigrees. A four-generation Italian family and a second Italian kindred harbor distinct missense variants that segregate with disease in all affected members ([PMID:21827917]). Screening of 366 European families negative for common triplet expansions identified nine unrelated index cases (2.6%) with six different missense changes in exons 15–16 of AFG3L2, all segregating with ataxia ([PMID:20725928]). Private heterozygous variants, including c.2065T>C (p.Tyr689His) and c.1996A>G (p.Met666Val), have been reported in multiple SCA28 patients, confirming a mutational hotspot in the proteolytic domain ([PMID:24293060]).

The variant spectrum in SCA28 is dominated by missense substitutions (n>20) clustered in the C-terminal protease domain, with occasional frameshift and nonsense alleles reported. One representative hotspot mutation is c.2065T>C (p.Tyr689His) ([PMID:24293060]). Phenotypic variability includes juvenile or adult onset, cerebellar atrophy, dysarthria, nystagmus, slow saccades, and brisk deep tendon reflexes (HP:0001260; HP:0000639; HP:0000514; HP:0001347).

Functional studies across models concordantly show that AFG3L2 missense alleles impair m-AAA complex assembly and protease activity. Yeast complementation assays of p.Tyr616Cys reveal hypomorphic oligomerization defects in m-AAA complexes ([PMID:22022284]). Afg3l2–/– and missense mouse models exhibit axonal development defects, delayed myelination, and Purkinje cell vulnerability ([PMID:18337413]). Patient fibroblasts with p.Val723Met and p.Tyr689His show mitochondrial fragmentation, reduced calcium uptake, and OPA1 processing defects, all rescued by OPA1 overexpression ([PMID:22678058]).

Structural cryo-EM of human AFG3L2 elucidates how disease variants disrupt unique substrate-handling interfaces, linking genotype to altered ATP-dependent translocation and proteolysis ([PMID:31327635]). Across studies, haploinsufficiency and dominant-negative effects converge on mitochondrial network fragmentation and defective quality control in neurons.

Collectively, definitive genetic and functional evidence supports AFG3L2 as the causative gene for SCA28, justifying clinical testing of AFG3L2 in patients with undiagnosed autosomal dominant ataxia accompanied by oculomotor slowing and brisk reflexes. Early molecular diagnosis enables genetic counseling, prognostication, and future therapeutic targeting of m-AAA protease function.

References

• Nature genetics • 2010 • Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. PMID:20208537
• Human mutation • 2010 • Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxia PMID:20725928
• Journal of molecular neuroscience • 2014 • A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28. PMID:24293060
• PLoS genetics • 2011 • Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PMID:22022284
• The Journal of neuroscience • 2008 • The mitochondrial protease AFG3L2 is essential for axonal development. PMID:18337413
• Molecular cell • 2019 • Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease. PMID:31327635

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