HINT1 neuropathy in Norway: clinical, genetic and functional profiling

• Published in: Orphanet journal of rare diseases Vol. 16; no. 1; p. 116
• Main Authors: Amor-Barris, Silvia, Høyer, Helle, Brauteset, Lin V, De Vriendt, Els, Strand, Linda, Jordanova, Albena, Braathen, Geir J, Peeters, Kristien
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04.03.2021; BioMed Central; BMC
• Subjects: Age; Causes of; Central nervous system; Charcot-Marie-Tooth Disease; Electromyography; Epidemiology; Europe; Foot drop; Gait; Genetic aspects; Genetic research; Genetic variation; Hands; Haplotypes; HINT1; Humans; Legs; Medical research; Mutation; Nerve Tissue Proteins - genetics; Neuromyotonia; Neuropathies, Hereditary motor and sensory; Norway; Norway - epidemiology; Pain; Patients; Peripheral Nervous System Diseases - epidemiology; Peripheral Nervous System Diseases - genetics; Peripheral neuropathy; Proteins; Rare diseases; Statistics; Turkey; Norway; Europe; Turkey; Russia; Neuromyotonia; HINT1; Peripheral neuropathy; Norway; Charcot-Marie-Tooth disease
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-021-01746-z

Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.