A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease

Diodato, Daria; Tasca, Giorgio; Verrigni, Daniela; D’Amico, Adele; Rizza, Teresa; Tozzi, Giulia; Martinelli, Diego; Verardo, Margherita; Invernizzi, Federica; Nasca, Alessia; Bellacchio, Emanuele; Ghezzi, Daniele; Piemonte, Fiorella; Dionisi‐Vici, Carlo; Carrozzo, Rosalba; Bertini, Enrico

doi:10.1038/ejhg.2015.141

Cited by 47 publications

(50 citation statements)

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“…In a recent study on the effect of several AIFM1 mutations on protein structure and function, one mutation situated in close vicinity to the mutations described here, p.(Val243Leu), had virtually no effect on the folding, redox, and DNA-binding properties of the protein [18]. 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].…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…While affected residues are distributed throughout AIF, many occur in locations linked to CTC formation, including the NADH binding site (G308E and G338E) (Berger et al, 2011; Diodato et al, 2016), dimerization interface (R422W, R422Q, R430C, A472V, P475L) (Zong et al, 2015), C-loop salt bridges (ΔR201) (Ghezzi et al, 2010), and the cavity shielded by the Cβ-clasp (E493V) (Rinaldi et al., 2012). Among disease-related mutants studied in vitro , efficiency of CTC formation varies (enhanced, reduced, or unchanged relative to wild-type).…”

Section: Discussionmentioning

confidence: 99%

“…NADH binding is required for AIF’s interaction with mitochondrial import factor CHCHD4 (Hangen et al, 2015). Disease-causing mutations that hinder AIF’s ability to efficiently maintain a CTC with NADH lead to human neurodegenerative mitochondriopathies (Berger et al, 2011; Diodato et al, 2016; Ghezzi et al, 2010; Rinaldi et al, 2012; Zong et al, 2015). These interaction and disease-causing results suggest that AIF’s structural transitions are key for mitochondrial homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor

Brosey

Long

et al. 2016

Structure

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SUMMARY Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos: these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. Here we define molecular pathways linking AIF’s active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communication networks using molecular dynamics simulations. Collective results identify two pathways propagating allostery from the CTC active site: 1) active site H454 links to S480 of AIF’s central β-strand to modulate a hydrophobic border at the dimerization interface and 2) an interaction network links AIF’s FAD cofactor, central β-strand, and Cβ-clasp whereby R529 reorientation initiates C-loop release during CTC formation. This knowledge of AIF allostery and its flavoswitch mechanism provides a foundation for biologically understanding and biomedically controlling its participation in mitochondrial homeostasis and cell death.

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“…10 Cerebellar ataxia, mostly of childhood onset, has been occasionally reported in association with other phenotypes of variable severity. 6,8,10,11 In this article, we extend the spectrum of AIFM1-related phenotypes and report a novel AIFM1 mutation affecting the NAD(H) binding site.…”

Section: Discussionmentioning

confidence: 94%

Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation

Pandolfo¹,

Rai²,

Remiche

et al. 2020

Neurol Genet

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ObjectiveTo describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome.MethodsWe studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an AIFM1 variant identified by CES and demonstrate its pathogenicity.ResultsThe proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the AIFM1 gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance.ConclusionsOur report extends the molecular and phenotypic spectrum of AIFM1 mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.

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A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease

Cited by 47 publications

References 13 publications

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

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

Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor

Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation

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