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AFG3L2 is a zinc metalloprotease and an ATPase localized in an inner mitochondrial membrane involved in mitochondrial quality control of several nuclear- and mitochondrial-encoded proteins. Mutations in AFG3L2 lead to diseases like slow progressive ataxia, which is a neurological disorder. This review delineates the cellular functions of AFG3L2 and its dysfunction that leads to major clinical outcomes, which include spinocerebellar ataxia type 28, spastic ataxia type 5, and optic atrophy type 12. It summarizes all relevant AFG3L2 mutations associated with the clinical outcomes to understand the detailed mechanisms attributable to its structure-related multifaceted roles in proteostasis and quality control. We face early diagnostic challenges of ataxia and optic neuropathy due to asymptomatic parents and variable clinical manifestations due to heterozygosity/homozygosity of AFG3L2 mutations. This review intends to promote AFG3L2 as a putative prognostic or diagnostic marker. Functions, mutations, and clinical manifestations in AFG3L2, a mitochondrial AAA + ATPases. [ABSTRACT FROM AUTHOR]

Purpose: To highlight the importance of the utility of clinical exome sequencing, and show how it led to the diagnosis of nonsyndromic autosomal dominant optic atrophy arising from an autosomal dominant variant in AFG3L2. Observations: A healthy father and daughter of East African heritage experienced the onset of vision loss in the first decade of life due to optic atrophy. No additional neurologic or neuroimaging abnormalities were detected. Clinical exome sequencing was initially performed and provided a negative result. Reanalysis of the sequencing data revealed an autosomal dominant pathogenic variant in AFG3L2, c.1064C>T (p.Thr355Met), a gene that was recently identified to be associated with non-syndromic optic atrophy. This variant has previously been reported in a patient with optic atrophy, motor disturbances, and an abnormal brain MRI. Conclusions: As the causes of dominant optic atrophy continue to expand, accurate genetic diagnosis is aided by an iterative reanalysis process for individuals and families when initial exome and genome testing does not provide an answer.

Keywords: spasmodic dysphonia; ATX-AFG3L2; SCA28; AFG3L2; ataxia EN spasmodic dysphonia ATX-AFG3L2 SCA28 AFG3L2 ataxia 1024 1026 3 06/20/23 20230601 NES 230601 Heterozygous pathogenic variants in ATPase family gene 3-like 2 ( I AFG3L2 i ) gene are associated with autosomal dominant cerebellar ataxia (ATX- I AFG3L2 i ), previously known as spinocerebellar ataxia type 28, which typically presents with slowly progressive cerebellar ataxia, dysarthria, oculomotor abnormalities, and pyramidal signs.[[1]] Carriers of compound heterozygous I AFG3L2 i variants may demonstrate other features including ptosis, optic atrophy, external ophthalmoplegia, generalized dystonia, and lingual dyskinesia.[[3], [5]] Here, we report an individual with a rare compound heterozygous I AFG3L2 i variant who uniquely presented with spasmodic dysphonia, along with other typical features of ATX- I AFG3L2 i . Spasmodic Dysphonia in a Patient with Spinocerebellar Ataxia Associated with a Rare AFG3L2 Variant (ATX-AFG3L2) ATX-AFG3L2, spasmodic dysphonia, AFG3L2, SCA28, ataxia. [Extracted from the article]

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but adult mice showed signs of cerebellar ataxia detectable by beam test. Although cerebellar pathology was negative, electrophysiological analysis showed a trend towards increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was altered, with greatly reduced expression of fusogenic Opa1 isoforms. Mitochondrial alterations were also detected in cerebella of 18-month-old heterozygous mutants and may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.

Abstract Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m -AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but adult mice showed signs of cerebellar ataxia detectable by beam test. Although cerebellar pathology was negative, electrophysiological analysis showed a trend towards increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was altered, with greatly reduced expression of fusogenic Opa1 isoforms. Mitochondrial alterations were also detected in cerebella of 18-month-old heterozygous mutants and may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development. Graphical abstract Unlabelled Image Highlights • We generated a knock-in mouse model of SCA28 harbouring a p.Met665Arg -Afg3l2 allele. • Homozygous mutants died perinatally with evidence of cardiac atrophy. • Heterozygous mice developed normally but presented late-onset cerebellar ataxia. • MEFs showed altered mitochondrial bioenergetics and dynamics. • Proteotoxicity is suggested to be responsible for SCA28 pathogenesis. [ABSTRACT FROM AUTHOR]

Keywords: AFG3L2; SCA28; SPG7; Eye-of-the-tiger; Exome sequencing EN AFG3L2 SCA28 SPG7 Eye-of-the-tiger Exome sequencing 52 54 3 06/16/20 20200401 NES 200401 The eye-of-the-tiger (EOT) is a neuroradiologic sign observed on T2-weighted sequences that refers to a central high signal intensity in the anteromedial aspect of both globus pallidus (GP) and a surrounding low signal intensity due to excess iron deposition. Heterozygous mutations in AFG3L2 cause spinocerebellar ataxia 28 (SCA28) which manifests with ataxia, ophthalmoparesis, and cerebellar atrophy that begins in young adults and has a very slow clinical progression [3]. [Extracted from the article]

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 28 (SCA28) is an autosomal dominant neurodegenerative disorder caused by missense AFG3L2 mutations. To examine the occurrence of SCA28 in the Czech Republic, we screened 288 unrelated ataxic patients with hereditary ( N = 49) and sporadic or unknown ( N = 239) form of ataxia for mutations in exons 15 and 16, the AFG3L2 mutation hotspots. A single significant variant, frameshift mutation c.1958dupT leading to a premature termination codon, was identified in a patient with slowly progressive speech and gait problems starting at the age of 68 years. Neurological examination showed cerebellar ataxia, mild Parkinsonian features with predominant bradykinesia, polyneuropathy of the lower limbs, and cognitive decline. However, other common SCA28 features like pyramidal tract signs (lower limb hyperreflexia, positive Babinski sign), ophthalmoparesis or ptosis were absent. The mutation was also found in a patient's unaffected daughter in whom a targeted examination at 53 years of age revealed mild imbalance signs. RNA analysis showed a decreased ratio of the transcript from the mutated AFG3L2 allele relative to the normal transcript in the peripheral lymphocytes of both patients. The ratio was increased by puromycin treatment, indicating that the mutated transcript can be degraded via nonsense-mediated RNA decay. The causal link between the mutation and the phenotype of the patient is currently unclear but a pathogenic mechanism based on AFG3L2 haploinsufficiency rather than the usual dominant-negative effect of missense AFG3L2 mutations reported in SCA28, cannot be excluded. [ABSTRACT FROM AUTHOR]

SCA28 is caused by mutations in the AFG3L2 gene. This gene encodes a subunit of the mitochondrial metalloprotease AFG3L2 (AFG3-like protein 2). Clinical features of SCA28 include slow to moderate progressive ataxia, dysarthria, and additional symptoms such as nystagmus, slow saccades, and increased deep tendon reflexes. Here, we report on a novel AFG3L2 mutation in a patient with slowly progressive ataxia and a positive family history. The nucleotide change results in the substitution of an evolutionarily highly conserved tyrosine by histidine (p.Y689H) in the M41 peptidase domain of AFG3L2. [ABSTRACT FROM AUTHOR]

Background: SCA28 is an autosomal dominant ataxia associated with AFG3L2 gene mutations. We performed a whole genome expression profiling using lymphoblastoid cell lines (LCLs) from four SCA28 patients and six unrelated healthy controls matched for sex and age. Methods: Gene expression was evaluated with the Affymetrix GeneChip Human Genome U133A 2.0 Arrays and data were validated by real-time PCR. Results: We found 66 genes whose expression was statistically different in SCA28 LCLs, 35 of which were up-regulated and 31 down-regulated. The differentially expressed genes were clustered in five functional categories: (1) regulation of cell proliferation; (2) regulation of programmed cell death; (3) response to oxidative stress; (4) cell adhesion, and (5) chemical homeostasis. To validate these data, we performed functional experiments that proved an impaired SCA28 LCLs growth compared to controls (p < 0.005), an increased number of cells in the G0/G1 phase (p < 0.001), and an increased mortality because of apoptosis (p < 0.05). We also showed that respiratory chain activity and reactive oxygen species levels was not altered, although lipid peroxidation in SCA28 LCLs was increased in basal conditions (p < 0.05). We did not detect mitochondrial DNA large deletions. An increase of TFAM, a crucial protein for mtDNA maintenance, and of DRP1, a key regulator of mitochondrial dynamic mechanism, suggested an alteration of fission/fusion pathways. Conclusions: Whole genome expression profiling, performed on SCA28 LCLs, allowed us to identify five altered functional categories that characterize the SCA28 LCLs phenotype, the first reported in human cells to our knowledge. [ABSTRACT FROM AUTHOR]

Autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Genetically, 26 different loci have been identified so far, although the corresponding gene has not yet been determined for 10 of them. Recently, mutations in the ATPase family gene 3-like 2 gene were presented to cause SCA type 28. To define the frequency of SCA28 mutations, we performed molecular genetic analyses in 140 unrelated familial cases with ataxia. Among other variations, we found a novel missense mutation at an evolutionarily conserved amino-acid position using a single-strand conformation polymorphism approach, followed by DNA sequencing. This amino-acid exchange p.E700K was detected in a four-generation German family and was not observed in a survey of 400 chromosomes from healthy control individuals. [ABSTRACT FROM AUTHOR]

We have recently mapped the spinocerebellar ataxia type 28 (SCA28) locus on chromosome 18p11.22 in a four-generation Italian family. The clinical phenotype in affected individuals of this family was characterized by juvenile onset, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia at lower limbs, nystagmus, and ophthalmoparesis. The mean age at onset was 19.5 years, and no evidence of anticipation between generations was observed. The disease locus on chromosome 18p11.22-q11.2 was found to span a region of 7.9 Mb of genomic DNA. Direct sequencing of candidate genes within the critical interval led to the identification of a heterozygous point mutation in one of them. The mutation was located in a highly conserved domain with proposed functional properties in the protein product of the SCA28 gene, and segregated with the disease phenotype in all affected members of this family. Thereafter we have screened 105 patients with autosomal dominant spinocerebellar ataxia who had resulted negative for mutations in known SCA genes. Genetic screening allowed the identification in a second Italian family of a distinct missense mutation located in the very same functional domain of the protein. The affected members of this second family exhibited a neurological phenotype similar to that of the original family. Both mutations, not found in more than 500 chromosomes, are associated with amino acid changes (Glu→Lys and Ser→Leu, respectively) in evolutionarily conserved residues of the alleged SCA28 gene. Our data point to a putative pathogenic role of these mutations, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations. [ABSTRACT FROM AUTHOR]

The AFG3L2 gene encodes AFG3-like protein 2, which is a subunit of human mitochondrial ATPases associated with various cellular protease activities (m-AAA). The clinical spectrum of AFG3L2 mutations is broad. Dominant AFG3L2 mutations can cause autosomal dominant spinocerebellar ataxia type 28 (SCA28), whereas biallelic AFG3L2 mutations may lead to spastic ataxia 5 (SPAX5). However, the role of AFG3L2 mutations in autosomal recessive spinocerebellar ataxia (SCAR) remains elusive. The aim of this study is to delineate the clinical features and spectrum of AFG3L2 mutations in a Taiwanese cohort with cerebellar ataxia. Mutational analyses of AFG3L2 were carried out by targeted resequencing in a cohort of 133 unrelated patients with molecularly undetermined cerebellar ataxia. We identified one single patient carrying compound heterozygous mutations in AFG3L2 , p.[R632*];[V723M] (c.[1894C > T];[2167G > A]). The patient has suffered from apparently sporadic and slowly progressive cerebellar ataxia, ptosis, and ophthalmoparesis since age 55 years. These findings expand the clinical spectrum of AFG3L2 mutations and suggest a new subtype of late-onset SCAR caused by biallelic AFG3L2 mutations. [Display omitted] • Biallelic AFG3L2 mutations cause autosomal recessive cerebellar ataxias (SCARs). • AFG3L2 -related ataxias are rare in Asia. • Ataxia, ptosis, ophthalmoparesis, and hyperreflexia, hint AFG3L2 -related ataxias. [ABSTRACT FROM AUTHOR]

Autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Nearly 33 genetically distinct subtypes have been defined, and 19 seemingly unrelated disease genes have been identified so far. Recently, mutations in the ATPase family gene 3-like 2 (AFG3L2) gene were presented to cause SCA28 subtype. In order to define the frequency of SCA28 mutation in Chinese mainland, we performed molecular genetic analysis in 67 unrelated affected individuals with ADCA. At last, we did not find AFG3L2 gene mutation, except for three known single nucleotide polymorphisms (SNP)s. It suggests that SCA28 subtype is very rare in Chinese mainland. [ABSTRACT FROM AUTHOR]