HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report

Abstract

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HINT1 neuropathy: Expanding the genotype and phenotype spectrum

“…From a clinical point of view, we observed scoliosis in 3/7 (43%) of the patients, which is consistent with the data in the literature 6/11 (55%) 20,21 . We notice foot abnormalities in 6/7 patients (86%) as described in the literature 29/34 (85%) 12,19–25 …”

“…First, the founder variant c.110G>C p.(Arg37Pro) is described in ARAN‐NM in 89 families, at a homozygous state for 77 of them, from all around the world (Eastern Europe, Asia, and South America). It is the most frequent variant in every studied population, except for Chinese and Belgian cohorts 12,16 . Herein, we report three homozygous patients (43%) carriers of this variant originating from Austria, Kosovo, and France (P1‐P3‐P4).…”

“…as described in the literature 29/34 (85%). 12,[19][20][21][22][23][24][25] Serum CK level was increased for 26/39 (67%) published patients 2,12,14,20,[24][25][26][27] and for 5/6 (83%) of ours (data unavailable for patient P3). In average, CK serum levels was up to 3.5 N which might led to suspect a myopathic process.…”

“…10 To date, 128 patients with ARAN-NM have been described (108 families) worldwide. [11][12][13][14][15] Most of them are from eastern Europe, where the founder variant (c.110G>C, p.Arg37Pro) is mainly represented allele frequency 0.00043 in the European (Non-finish) population (gnomAD V3.1.2), 0.002 in Russia. 15 In addition, another founder variant (c.112T>C, p.Cys38Arg) has been identified in the Chinese population.…”

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

“…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 …”