Further Evidence for the Implication of the <b><i>MET</i></b> Gene in Non-Syndromic Autosomal Recessive Deafness

Abstract

Mutations in the mesenchymal epithelial transition factor (&lt;i&gt;MET&lt;/i&gt;) gene are frequently associated with multiple human cancers but can also lead to human non-syndromic autosomal recessive deafness (DFNB97). In the present study, we identified a novel homozygous missense mutation in the &lt;i&gt;MET&lt;/i&gt;gene causing a non-syndromic hearing impairment DFNB97 form. Whole-exome sequencing was performed to determine the genetic causes of hearing loss in a Moroccan consanguineous family with an affected daughter. The structural analysis of native and mutant in the SEMA domain of the MET receptor was investigated using a molecular dynamics simulation (MDS) approach. We identified a novel pathogenic homozygous c.948A&amp;#x3e;G (p.Ile316Met) mutation in the &lt;i&gt;MET&lt;/i&gt; gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment. The results of the MDS approach show that an Ile316Met mutation in the SEMA domain leads to protein flexibility loss. This may produce a major impact on the structural conformation of the MET receptor, which also affects the function and binding site of the receptor. This is the first time that a mutation in the &lt;i&gt;MET&lt;/i&gt; gene is described in a Moroccan family. Moreover, this study reports the second family in the world associating deafness and mutation in the &lt;i&gt;MET&lt;/i&gt; gene.

Alternative splicing in shaping the molecular landscape of the cochlea

“…Considering that all three pathogenic variants reduce the inclusion of exon 5a, functional differences among the various isoforms may also contribute to tissue specificity. We must also consider mutations in the MET gene, which encodes an HGF receptor, mutations of which can lead to non-syndromic hearing loss (DFNB97) (Mujtaba et al, 2015;Bousfiha et al, 2019). As HGF-MET signaling is implicated in a myriad of biological processes (Baldanzi and Graziani, 2015), it is surprising that mutations of both HGF and MET can show such tissue-specific effects on the cochlea.…”

HGF and MET: From Brain Development to Neurological Disorders

“…A rare MET missense genetic mutation (c.2575T > G p.Phe859Val) was reported in Pakistani family patients segregating with DFNB97 deafness ( Mujtaba et al, 2015 ). Recently, another MET mutation was found in a Moroccan bilateral DFNB97 deaf patient, consisting of a homozygous missense mutation (c.948A > G; p.Ile316Met) of MET, affecting a highly conserved residue in the SEMA domain ( Bousfiha et al, 2019 ).…”