Whole exome sequencing identifies a novel variant in an apoptosis-inducing factor gene associated with X-linked recessive hearing loss in a Chinese family

Abstract

We report on the genetic analysis of a Chinese family in which four male patients presented with postlingual progressive hearing loss, associated with distal muscle wasting and unsteady ataxic gait. Using whole exome sequencing, we identified a new pathogenic variant (c.1463C>T, p.Pro488Leu) in the AIFM1 gene, which encodes the apoptosis-inducing factor mitochondrion-associated 1 precursor. AIFM1 is involved in the mitochondrial respiratory chain and cellular caspase-independent apoptosis pathway and has been reported to cause multiple phenotypes including hearing loss. The p.Pro488Leu missense variant segregated with symptoms in the pedigree. It was not found in the dbSNP database, databases of genomes and SNPs in the Chinese population, in 74 patients with sporadic hearing loss, or in 108 normal individuals.We also verified that this AIFM1variant enhanced cell apoptosis rates compared in 293T cells transfected with wild-type AIFM1. Different variations of AIFM1 give rise to different phenotypes in patients, and this is the second reported family with a variant in the C-terminal domain of AIFM1 showing the phenotype of hearing loss and peripheral neuropathy.

Identification of a novel AIFM1 variant from a Chinese family with auditory neuropathy

“…A study of AIFM1 p. P488L variants in auditory neuropathy and peripheral neuropathy showed that AIFM1 p. P488L variants caused a mild increase in the rate of caspase-independent apoptosis in cells ( Wang et al, 2019 ). Because the immunofluorescence and WB assays showed that the p. D456G variant reduced AIFM1 protein expression, the Tunel assay was performed to evaluate its adverse effect on cell survival.…”

“…For example, a follow-up study found that some AN patients initially showed a low-frequency ascending hearing pattern, but with the progress of the disease, their highfrequency hearing was decreased rapidly to show a descending hearing pattern (Wang et al, 2020). Furthermore, some AN patients present with a descending hearing pattern involving the full frequency were accompanied by severe motor development impairment and mental retardation (Wang et al, 2019). Frontiers in Genetics frontiersin.org Furthermore, consistent with previous studies (Wang and Starr, 2018), the threshold of ASSR results in our study was also significantly higher than that of PTA (Figure 1D).…”

AIFM1 beyond cell death: An overview of this OXPHOS-inducing factor in mitochondrial diseases

“… 88 , 94 , 95 , 96 , 97 , 98 As additional two groups, we can mention 4 AIF variants (Q235H, D237G/V, D240D synonymous substitution) that can give rise to a X-linked developmental disorder consisting of progressive skeletal and neurologic abnormalities, 99 , 100 , 101 , 102 , 103 while the other 4 recently identified AIF mutants (G399S, E453Q, P488L, Y492H) have been linked to mitochondrial diseases with a variable spectrum of phenotypic outcomes ( Table 1 ). 104 , 105 , 106 , 107 At the time of writing, a new case of fatal encephalomyopathy has been reported in an infant from a mother carrying a de novo AIFM1 intronic mutation that is supposed to alter the correct splicing of the precursor mRNA. 108 Due to exon 11 skipping and the consequent amino acid frameshift, the predicted AIF variant is a truncated polypeptide of 361 amino acids that, if translated, is unstable and rapidly degraded.…”