Novel Mutation in <b><i>AIFM1</i></b> Gene Associated with X-Linked Deafness in a Moroccan Family

Abstract

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We found a disease-segregating mutation in the X-linked &lt;i&gt;AIFM1&lt;/i&gt; gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The impact of the c.1045A&amp;#x3e;G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; To our knowledge, this is the first study that identifies a mutation in the &lt;i&gt;AIFM1&lt;/i&gt; gene in Moroccan patients suffering from X-linked auditory neuropathy.

A Signature of Three Apoptosis-Related Genes Predicts Overall Survival in Breast Cancer

“…As a conservative redox switch, it measures the metabolic state of mitochondria and turns it into a binary life/death solution ( 28 ). The product of this gene induces mitochondria to release cytochrome c and caspase-9, which are pro-apoptotic proteins ( 29 , 30 ). In the study of liver cancer, it was found that the full-length apoptosis-inducing factor mitochondrial-associated 1 ( AIFM1 ) (∼67 kDa) was cleaved at its N-terminus to produce truncated AIFM1 (∼57 kDa), which was not dependent on caspase Enzymes induce apoptosis, overexpression of full-length AIFM1 can induce caspase-dependent apoptosis and inhibit cell growth of liver cancer cells, our data reveal the potential role of rAd- AIFM1 in HCC gene therapy ( 31 ).…”

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

“…88,89 Mutations linked to auditory defects X-linked deafness. [109][110][111] Patients became symptomatic at different age. In a few cases, auditory neuropathy could be associated with other manifestations.…”

“…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. 108 Finally, a large number of AIF variants has been associated with relatively mild syndromes primarily characterized by progressive auditory neuropathy and deafness 109 , 110 , 111 ( Table 1 ), which may indicate that these mutations have a weaker effect on the OXPHOS system compared to the first disease-causing AIFM1 allele identified more than a decade ago. 85 Given the relevance of AIF in human pathophysiology, we envision that a better characterization of these clinically relevant AIF variants at biophysical, biochemical and cellular levels may help to further improve our understanding of the complex biology of AIF and its contribution to mitochondrial bioenergetics.…”

“… 88 , 89 Mutations linked to auditory defects - p.Thr260Ala - - p.Ile304Met p.Leu333Phe p.Leu344Phe p.Ser349Gly p.Gly360Arg p.Arg422Trp p.Arg422Gln p.Arg430Cys p.Arg451Gln p.Ala465Val p.Ala472Val p.Pro475Leu p.Pro488Leu p.Val498Met p.Tyr560His p.Ile591Met c.547A>T c.778A>G c.881G>A c.890A>T c.912C>G c.997C>T c.1030C>T c.1045A>G c.1078G>C c.1264C>T c.1265G>A c.1288C>T c.1352G>A c.1394C>T c.1415C>T c.1424C>T c.1463C>T c.1492G>A c.1678T>C c.1773C>G X-linked deafness. 109 , 110 , 111 Patients became symptomatic at different age. In a few cases, auditory neuropathy could be associated with other manifestations.…”

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

“…Three members of a family presenting with a complex syndrome (cerebellar ataxia and atrophy, mood and behavioural disorder, intellectual disability with or without hearing loss or peripheral neuropathy), were found to carry the p.G399S mutation in the NADH binding domain of AIFM1 [ 60 ]. Finally, a Moroccan family suffering from X-linked auditory neuropathy was found to harbour a missense variant (p.S349G) in the AIFM1 gene [ 61 ] ( Table 1 ). It is interesting to note that apart from the decreased OXPHOS activities identified in some of the patients and although some studies on AIFM1 function have been performed in vitro [ 45 , 47 , 132 ] or animal models [ 133 , 134 ], there is little evidence of the impact of these variants on the MIA40 function regulation by AIFM1 in these patients.…”