Different missense mutations of the optic atrophy 1 gene (OPA1
) identified in optic atrophy patients with auditory neuropathy spectrum disorder (ANSD
) induce functional impairment through different molecular mechanisms.
is the gene responsible for autosomal dominant optic atrophy (ADOA
), but some of its mutations are also associated with ANSD
is a member of the GTPase
family of proteins and plays a key role in the maintenance of mitochondrial activities that are dependent on dimer formation of the protein. There are many reports of OPA1
mutations, but the molecular mechanisms of their functional impairments are unclear.
The sequences of coding regions in OPA1
were analyzed from blood samples of ADOA
patients with ANSD
. Molecular modeling of the protein's ability to form dimers and its GTP-binding ability were conducted to study the effects of structural changes in OPA1
caused by two identified mutations and their resultant effects on protein function.
Two heterozygous mutations, p.T414P (c.1240A>C) and p.T540P (c.1618A>C), located in the GTPase
and middle domains of OPA1
, respectively, were identified in two patients. Molecular modeling indicated decreased dimer formation caused by destabilization of the association structure of the p.T414P mutant, and decreased GTP-binding caused by destabilization of the binding site structure in the p.T540P mutant.
These two different conformational changes might result in decreased GTPase
activities that trigger ADOA
associated with ANSD
, and are likely to be associated with mild clinical features. Molecular modeling would provide useful information in clinical practice.