Case Report: A Novel Intronic Mutation in AIFM1 Associated With Fatal Encephalomyopathy and Mitochondrial Disease in Infant

Abstract

BackgroundThe AIFM1 gene is located on chromosome Xq26.1 and encodes a flavoprotein essential for nuclear disassembly in apoptotic cells. Mutations in this gene can cause variable clinical phenotypes, but genotype-phenotype correlations of AIFM1-related disorder have not yet been fully determined because of the clinical scarcity.Case PresentationWe describe a 4-month-old infant with mitochondrial encephalopathy, carrying a novel intronic variant in AIFM1 (NM_004208.4: c.1164 + 5G > A). TA cloning of the complementary DNA (cDNA) and Sanger sequencing revealed the simultaneous presence of an aberrant transcript with exon 11 skipping (89 bp) and a normal transcript through analysis of mRNA extracted from the patient’s fibroblasts, which is consistent with direct RNA sequencing results.ConclusionWe verified the pathogenic effect of the AIFM1 c.1164 + 5G > A splicing variant, which disturbed normal mRNA splicing. Our findings expand the mutation spectrum of AIFM1 and point out the necessity of intronic sequence analysis and the importance for integrative functional studies in the interpretation of sequence variants.

Expanding the spectrum of neonatal‐onset AIFM1‐associated disorders

“…In addition to altered properties, various missense amino acid changes have been proved to cause protein instability in a subset of AIFM1 cases; the degree of AIFM1 reduction is therefore another possible modulator of phenotype spectrum and severity. 30 The novel c.5T>C; p.(Phe2Ser) variant described here is the first variant in AIFM1 located in the MTS. It putatively affects the ability of AIFM1 to correctly localize to the mitochondria; however, experimental studies did not show any evidence of impaired processing or mislocalization of the AIFM1 protein.…”

“…Early-onset, drug-resistant seizures have already been described in neonates harbouring AIFM1 mutants (Table S2). 30,31 However, this is the first case presenting with diffuse white matter signal alteration and relative sparing of basal ganglia. We may speculate that partuminduced stress exacerbated the bioenergetic failure that eventually led to such a diffuse involvement, which has not been reported in other cases.…”

“…Intriguingly, Diodato at al suggested that different amino acid substitutions within the same region may in fact exert a variable effect on the oxidized vs reduced state of the AIFM1 protein, 39,40 hence affecting not only its redox properties but also protein stability and conformational changes (i.e., monomeric vs dimeric). In addition to altered properties, various missense amino acid changes have been proved to cause protein instability in a subset of AIFM1 cases; the degree of AIFM1 reduction is therefore another possible modulator of phenotype spectrum and severity 30 …”

“…In addition to altered properties, various missense amino acid changes have been proved to cause protein instability in a subset of AIFM1 cases; the degree of AIFM1 reduction is therefore another possible modulator of phenotype spectrum and severity. 30 …”

Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant

“…AIFM1 point variants have rarely been reported to induce splicing variants. One recent case report verified a novel intronic point variant of AIFM1 , which caused abnormal RNA splicing and exon 11 skipping [ 56 ]. Presently, to determine whether the splicing variant was induced by the AIFM1 c.1265 G > A variant, we analyzed the splicing variant in gene-corrected samples and performed exon capture assays.…”