However, these bioinformatic predictions have not been confirmed experimentally. Grantham’s analysis of amino acid substitution suggests that the p.P153L change could be pathogenic (11). This is supported by conservation of this amino acid in all paralogs and orthologs identified in a wide range of species (Fig. ​(Fig.3).3).

The Pro to Leu change is close to a potential Inhibitors,research,lifescience,medical coiled domain in GDAP1. Whether this change affects the properties of the coiled domain is not known. Figure 3 Conservation of proline at GDAP1 position 153 across various species. Hs (Homo sapiens), Pp (Pongo pygmaeus), Mm (Mus musculus), Pt (Pan troglodytes), Bt (Bos taurus), Cf (Canis familiaris), Rn (Rattus norvegicus), Inhibitors,research,lifescience,medical Gg (Gallus gallus), Dr (Danio rerio … Discussion For recessive traits, homozygous mutations enable direct genotype/phenotype correlations in vivo whereas the interpretation of compound heterozygous alleles are confounded by potentially different contributions to the overall phenotype

by the distinct mutant alleles and the disease state representing some outcome of a combination of mutations. Limited information is available with respect to complete clinical, electrophysiological and neuropathological characterization of specific GDAP1 mutations. Even less is known Inhibitors,research,lifescience,medical regarding longitudinal clinical follow-up of patients with mutations in GDAP1. We identified a P153L homozygous missense mutation in a Polish patient with severe CMT, the product of a consanguineous parentage. The mutation occurs in a highly conserved proline close to a potential coiled domain and is likely to alter the structure of the GDAP1 protein. The electrophysiological studies were consistent with axonopathy. Neuropathology Inhibitors,research,lifescience,medical revealed mixed, but mostly axonal, changes with preservation of nerve fibres similar to those observed in two other patients (12). While some mutations in GDAP1 segregate with pure axonal neuropathies, there is currently no published morphological evidence for pure demyelinating CMT1 neuropathy. Inhibitors,research,lifescience,medical Even

within the same family, the patients harbouring identical GDAP1 mutation may manifest with axonal and demyelinating 17-DMAG (Alvespimycin) HCl neuropathy. In a consanguineous Turkish family, in which the R282C mutation in the GDAP1 gene was identified, axonal neuropathy was diagnosed in the proband, whereas a sister of the proband Silmitasertib in vivo manifested with demyelinating neuropathy (13). In the absence of an animal model (e.g. Gdap1 deficient mice), questions as to whether axonal or demyelinating changes play a primary role remain unanswered. GDAP1 is expressed both in neurons and Schwann cells, its protein product is localized in the mitochondrial outer membrane (9). Overexpression induces mitochondrial fragmentation without inducing apoptosis, a functional antithesis to mitofusin. Mutations of MFN2, that encodes mitofusin, are apparently one of the most common causes of inherited axonopathy (14, 15).