A novel mutation in HINT1 gene causes autosomal recessive axonal neuropathy with neuromyotonia, effective treatment with carbamazepine and review of the literature

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

“…Currently, 25 causal variants have been identified in over 100 NMAN-patients from Europe, Asia and America [ 1 , 2 , 9 – 12 ]. Haplotype analysis demonstrated founder effects for four of the recurrent HINT1 mutations in Europe [ 1 , 2 , 13 ] (p.Arg37Pro, p.Cys84Arg, p.Arg95Gln, p.His112Asn) and one in China [ 9 ] (p.Cys38Arg) explaining the elevated prevalence of NMAN in certain geographical areas.…”

Dynamic Long-Range Interactions Influence Substrate Binding and Catalysis by Human Histidine Triad Nucleotide-Binding Proteins (HINTs), Key Regulators of Multiple Cellular Processes and Activators of Antiviral ProTides

“…One reported missense mutation on the protein surface, I63N, stands out in the context of our study. 13 I63N lies immediately adjacent to Q62 and thus could potentially have an effect on active site function by a mechanism much like that studied here using Q62 variants; however, further experimentation is required.…”

“…Phosphorylation of hHINT1 Y109 has been shown to modulate the affinity of the binding interaction between hHINT1 and microphthalmia-associated transcription factor (MITF) with implications for the expression of the oncogenic genes for which the transcription factor is responsible. ,, Another example of the potential effects of surface residues near the water channel of hHINT1 is found in numerous clinical case reports and genomic analyses which reveal hHINT1 missense mutations as a direct cause of Charcot–Marie–Tooth disease (CMT). − CMT leads to axonal neuropathic pain and the hyperexcitable state of nerves known as neuromyotonia. One reported missense mutation on the protein surface, I63N, stands out in the context of our study . I63N lies immediately adjacent to Q62 and thus could potentially have an effect on active site function by a mechanism much like that studied here using Q62 variants; however, further experimentation is required.…”

“…hHINT1 resides in the cytosol, and active site inhibition of the enzyme in mouse models has been shown to both dramatically prevent and reverse opioid tolerance. , The pharmacologic impact of hHINT1 active site inhibitors is understood to originate from the disruption of a key origin of opioid tolerance, the cross-talk between the μ-opioid (MOR) and the N -methyl d -aspartate receptor (NMDAR). Clinical case studies involving numerous hHINT1 polymorphisms have established these variants as a direct cause of Charcot–Marie–Tooth disease, as well as yielding axonal neuropathy with neuromyotonia. − In some cases, these missense mutations cause amino acid residue changes at the active site, but some are also noted at the hHINT1 dimer interface as well as the protein surface away from the active site. − Outside of its role in the central nervous system (CNS), hHINT1 also helps regulate the microphthalmia transcription factor (MITF), which when dysregulated, has been shown to lead to melanoma and colon cancer. , While the active site of the enzyme is known to be crucial in the hHINT1–MITF protein–protein interaction, an important post-translational phosphorylation site distant from the hHINT1 active site (Y109) has also been shown to modulate the interaction, but clear mechanistic explanations have not yet emerged …”