HINT1 was first reported in relation to autosomal recessive Charcot-Marie-Tooth disease in 2012, characterized as an axonal neuropathy with neuromyotonia (Zimon et al., PMID: 22961002). Although neuromyotonia was initially defined as a core feature of the disorder, reports of probands without neuromyotonia indicated incomplete penetrance for this phenotype. At least twelve unique variants (e.g. missense, nonsense, frameshift, etc.) have been reported in humans, with the most common pathogenic variant c.110G>C (p.Arg37Pro) being a founder variant observed mainly in patients of Slavic origin (PMID: 31848916). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least ten probands in five publications (PMIDs: 26059562, 24105373, 25342199, 30001929, 22961002) and segregated with disease in four additional family members. These probands generally present with a primary axonal neuropathy characterized by gait impairment, progressive distal muscle weakness and atrophy, facial/foot deformities, and neuromyotonia. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, as the mutant proteins are unable to fulfill HINT1's signalling role in the central and peripheral nervous system (PMID: 33404983). This gene-disease association is supported by expression evidence, HINT1's biochemical function in the nervous system, and a series of functional studies performed on pathogenic variants in cell and animal models. Primary expression in the CNS and PNS indicates the crucial role that the protein fulfills, while loss of the sumolayse activity that HINT1 provides matches with the primary motor neuropathy phenotypes observed in probands (PMID: 31088288). Additionally, functional evaluation of all known pathogenic variants demonstrated a variety of altered functions including impaired thermal stability, disrupted dimer formation, and loss of interaction with SUMO1, CaM, and ICD Teneurin 1 (PMID: 33404983). In summary, HINT1 is definitively associated with autosomal recessive Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.