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

Abstract

Background Recessive loss-of-function variations in HINT1 cause a peculiar subtype of Charcot-Marie-Tooth disease: neuromyotonia and axonal neuropathy (NMAN; OMIM[#137200]). With 25 causal variants identified worldwide, HINT1 mutations are among the most common causes of recessive neuropathy. The majority of patients are compound heterozygous or homozygous for a Slavic founder variant (c.110G>C, p.Arg37Pro) that has spread throughout Eurasia and America. Results In a cohort of 46 genetically unresolved Lithuanian patients with suspected inherited neuropathy, we identified eight families with HINT1 biallelic variations. Most patients displayed sensorimotor or motor-predominant axonal polyneuropathy and were homozygous for the p.Arg37Pro variant. However, in three families we identified a novel variant (c.299A>G, p.Glu100Gly). The same variant was also found in an American patient with distal hereditary motor neuropathy in compound heterozygous state (p.Arg37Pro/p.Glu100Gly). Haplotype analysis demonstrated a shared chromosomal region of 1.9 Mb between all p.Glu100Gly carriers, suggesting a founder effect. Functional characterization showed that the p.Glu100Gly variant renders a catalytically active enzyme, yet highly unstable in patient cells, thus supporting a loss-of-function mechanism. Conclusion Our findings broaden NMAN’s genetic epidemiology and have implications for the molecular diagnostics of inherited neuropathies in the Baltic region and beyond. Moreover, we provide mechanistic insights allowing patient stratification for future treatment strategies.

In-depth characterization of HINT1 pathogenic variants

“…3 ). This was further justified by previous reports showing that protein stability can differ between the two cellular systems 31,33 . The stability studies in both HeLa and yeast cells showed that p.Arg37Pro, p.Cys38Arg, p.His51Arg, and p.Val97Met were highly unstable ( Fig.…”

“…Most of them have been identified in single families or isolated patients and often in compound heterozygous states with limited functional evidence of pathogenicity. Overall, there is in vivo data for only one-fourth of all HINT1 pathogenic variants 1,31,33 , while the impact of the rest of the variants has only been partially assessed in vitro 6,7 . Obtaining biological samples from the patients is not always possible, highlighting the need for standardized assays to test pathogenicity.…”