A slowly progressive mitochondrial encephalomyopathy widens the spectrum of
            <i>AIFM1</i>
            disorders

Ardissone, Anna; Piscosquito, Giuseppe; Legati, Andrea; Langella, Tiziana; Lamantea, Eleonora; Garavaglia, Barbara; Salsano, Ettore; Farina, Laura; Moroni, Isabella; Pareyson, Davide; Ghezzi, Daniele

doi:10.1212/wnl.0000000000001613

Cited by 58 publications

(43 citation statements)

References 7 publications

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“…AIFM1 is found in the inner mitochondrial membrane and has a dual role as an NADH oxidoreductase and regulator of apoptosis. A defect in AIFM1 can lead to a loss of prosurvival function associated with the assembly/stabilization of the mitochondrial electron transfer chain, resulting in promotion of the translocation of AIFM1 from mitochondria to the nucleus, and finally causing large-scale DNA cleavage (Ardissone et al, 2015;Polster, 2013). Cell-free systems also showed that AIFM1 could cause mitochondrial membrane permeabilization and trigger the release of cytochrome c, indicating that AIFM1 may be involved in a positive feedback loop of the apoptosis pathway (Susin et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Lee

Chang

et al. 2019

Molecular Oncology

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Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3 , SMAC , and BCL‐X , at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF , ATM , AIFM1 , NFKB1 , and API5 , was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro , either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Lee

Chang

et al. 2019

Molecular Oncology

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“…Even more intriguing, different variants in AIFM1 have previously been shown to be associated with diverse neurological disorders featuring intellectual disability, sensory hearing loss, neuropathy, and T2 hyperintensity in the striatum on magnetic resonance imaging (MRI), with some patients presenting with a mitochondrial phenotype and abnormalities in respiratory chain function [19]. Specific phenotypes include auditory neuropathy spectrum disorder [20], a severe X-linked mitochondrial encephalopathy [21, 22], and Cowchock syndrome, an axonal sensorimotor neuropathy with deafness and mental retardation [23, 24]. This suggests that there is a tight genotype-phenotype relationship, causing these different clinical manifestations.…”

Section: Discussionmentioning

confidence: 99%

X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

et al. 2017

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An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-017-0520-x) contains supplementary material, which is available to authorized users.

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“…Some patients with TTC19 mutations show bilateral HOD on MRI scans [9]. A male patient with an adult-onset mitochondrial disease associated with an AIFM1 mutation has recently been reported [10]. His brain MRI scan exhibited hyperintense lesions in the bilateral ION on proton density-weighted images.…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic olivary degeneration: A clinico-radiologic study

Konno

Broderick

Tacik

et al. 2016

Parkinsonism & Related Disorders

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Introduction The frequency and causes of hypertrophic olivary degeneration (HOD) are unknown. We compared the clinical and radiological characteristics of unilateral HOD and bilateral HOD. Methods We performed a search of a radiologic report database for patients who were radiologically diagnosed as having HOD. This database includes the patients examined at the Mayo Clinic in Florida and Arizona. We used the search terms “hypertrophic olivary degeneration,” “HOD,” and “olivary” in the reports recorded from 1995 to 2015. Pertinent medical records and magnetic resonance imaging (MRI) scans of the brain for those with HOD were reviewed retrospectively. Results We identified 142 MRI studies on 95 cases who had radiologically proven HOD, 39 cases had unilateral HOD and 56 with bilateral HOD. In symptomatic cases, the most common symptom was ataxia. Palatal tremor was observed in almost half of all HOD cases. While cerebrovascular diseases were the most frequent etiology in both types of HOD (n=24, 62% in unilateral; n=17, 30% in bilateral), more than half of bilateral HOD cases had an unknown etiology (52%, n=29), whereas only 13% (n=5) of the unilateral cases had an unknown etiology (χ2 test, P<0.001). The lesions of unilateral HOD had a tendency to improve radiologically over time, whereas those associated with bilateral HOD were likely to worsen (χ2 test, P<0.05). Conclusions Our study showed that bilateral HOD is more common than unilateral HOD. Half of bilateral HOD cases had no obvious cause and some worsened over time. This may implicate a possible primary neurodegenerative process.

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A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders

Cited by 58 publications

References 7 publications

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

Hypertrophic olivary degeneration: A clinico-radiologic study

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