Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias

Cagnoli, Claudia; Stevanin, Giovanni; Brussino, Alessandro; Barberis, Marco; Mancini, Cecilia; Margolis, Russell L.; Holmes, Susan E.; Nobili, Marcello; Forlani, Sylvie; Padovan, Sergio; Pappi, Patrizia; Zaros, Cécile; Leber, Isabelle; Ribaı̈, Pascale; Pugliese, Luisa; Assalto, Corrado; Brice, Alexis; Migone, Nicola; Dürr, Alexandra; Brusco, Alfredo

doi:10.1002/humu.21342

Cited by 81 publications

(72 citation statements)

References 47 publications

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“…Currently, the majority of mutations in the AFG3L2 gene have been reported to be associated with autosomal dominant spinocerebellar ataxia 28 (17,20) and autosomal recessive spastic ataxia 5 (21,22) (MIM no. 604581).…”

Section: Discussionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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Abstract.Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter-and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA. IntroductionAutosomal dominant optic atrophy (DOA) is a disorder that results from the degeneration of the optic nerve fibers (1). It is one of the most prevalent forms of inherited optic neuropathies, which are genetic conditions affecting the retinal ganglion cells whose axons constitute the optic nerve (2). DOA is an important cause of inherited visual failure and occurs equally among males and females (1). Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3). It is generally diagnosed during childhood and is characterized by loss of visual acuity, dyschromatopsia, visual field defects and optic nerve pallor with optic disc excavation (4).The majority of DOA cases (80%) are isolated (non-syndromic) while the remaining (20%) are syndromic (2). DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8). To date, 224 genes associated with optic atrophy are listed in the Human Phenotype Ontology (HPO) database, the majority presenting with neurological symptoms, such as ataxia, mental retardation and spastic paraplegia (9). Increasing evidence also indicates that other genes, in addition to yet unidentified genes, are involved (10). Yet, despite these advancements, more than half of DOA patients still await a genetic diagnosis (11). This shortcoming may be overcome using whole exome sequencing, which has the potential to define the molecular diagnosis of patients presenting with a negative result for mutations in the OPA1, OPA3, ACO2 and TMEM126A genes.In the current study, the exome of an Italian patient affected by isolated DOA was analyzed. By combining exome sequencing with phenotype-driven variant analysis, a heterozygous mutation was identified in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene. Notably, the p.R468C (c.1402C>T) mutation was recently described in a family ex...

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Section: Discussionmentioning

confidence: 99%

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Colavito¹,

Maritan²,

Suppiej³

et al. 2017

Biomedical Reports

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“…Exons 10, 15, 16 of AFG3L2 (SCA28), mapping to the AAA-domain (exon 10) and M41-protease domain of the AFG3L2 protein were screened in patients with hereditary spastic paraplegia for phenotype modifiers by direct sequencing, as previously described (Cagnoli et al, 2010). All mutations so far reported in patients with SCA28 are located in one of these exons (Cagnoli et al, 2010;Di Bella et al, 2010;Edener et al, 2010).…”

Section: Sca28 Analysismentioning

confidence: 99%

“…All mutations so far reported in patients with SCA28 are located in one of these exons (Cagnoli et al, 2010;Di Bella et al, 2010;Edener et al, 2010).…”

Section: Sca28 Analysismentioning

confidence: 99%

“…Very recently, heterozygous missense mutations in the AFG3L2 gene were found to cause spinocerebellar ataxia type 28 (SCA28; OMIM 610246) (Di Bella et al, 2010). The associated clinical characteristics of heterozygous SCA28 patients include pyramidal signs, ptosis and ophthalmoplegia (Cagnoli et al, 2010;Di Bella et al, 2010). Patients with homozygous Table 2 Clinical features of SPG7-positive probands with spastic gait [groups Elleuch et al, (2006) …”

Section: Spg7 Phenotype and Diagnostic Criteriamentioning

confidence: 99%

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Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Klebe¹,

Depienne²,

Gerber³

et al. 2013

Basal Ganglia

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Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.

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“…Several SCA28-causing missense mutations have been identified in the AFG3L2 gene (2)(3)(4). Moreover, homozygous mutations in AFG3L2 are responsible for a myoclonic epilepsy-ataxia-polyneuropathy syndrome of childhood (5).…”

Section: Introductionmentioning

confidence: 99%

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca¹,

Baseggio²,

Consolato³

et al. 2014

J. Clin. Invest.

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Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca2+ peaks, resulting in enhanced cytoplasmic Ca2+ concentrations, which subsequently triggers PC-DCD. This Ca2+-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca2+ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca2+ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca2+ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients

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Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias

Cited by 81 publications

References 47 publications

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

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