HINT1 neuropathy in Norway: clinical, genetic and functional profiling

Silvia Amor-Barris,Lin V Brauteset,Linda Strand,Geir J Braathen,Els De Vriendt,Albena Jordanova,Helle Høyer,Kristien Peeters

doi:10.1186/s13023-021-01746-z

Abstract

BackgroundAutosomal 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.ResultsIn 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.ConclusionOur findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

Highlights

Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional histidine triad nucleotide-binding protein 1 (HINT1)
To investigate the occurrence of HINT1 neuropathy in Norway, we analyzed a cohort of 748 patients with suspected peripheral neuropathy by next-generation sequencing targeting a panel of neuropathy genes
The two probands live in different states and a detailed genealogical investigation dating back to the great-grandparents of patient 1 (P1) and the grandparents of patient 2 (P2) did not reveal any common ancestors

Summary

Introduction

Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is 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. Loss-of-function alterations in the histidine triad nucleotide-binding protein 1 (HINT1) are associated with autosomal recessive axonal neuropathy with neuromyotonia (NMAN [MIM: 137200]) [1]. Nineteen variants have been causally associated with HINT1-neuropathy in over 100 patients from Europe, North America and Asia [1,2,3,4,5]. There are four proven founder variants in Europe (p.Arg37Pro, p.Cys84Arg, p.His112Asn) [1, 6] and China (p.Cys38Arg) [4]. Central and South-East Europe, Russia and Turkey [1, 6].

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