HINT1 – Charcot-Marie-Tooth Disease (HINT1-related Neuropathy)

Autosomal recessive biallelic variants in HINT1 cause a distinct subtype of Charcot-Marie-Tooth disease characterized by axonal neuropathy with neuromyotonia (ARAN-NM) (NMAN; MONDO:0015626). A landmark study in 33 families first established loss-of-function HINT1 mutations as causative for this phenotype (PMID:22961002). Subsequent population-based studies have confirmed this association across Europe, revealing both founder and private alleles.

Genetic series have identified HINT1 variants in diverse cohorts: 33 families with eight pathogenic alleles were described via linkage and next-generation sequencing in Nature Genetics (PMID:22961002). A Greek cohort of 42 autosomal recessive or sporadic axonal neuropathy cases uncovered 4 probands with biallelic HINT1 mutations—2 homozygous for c.110G>C (p.Arg37Pro) and 2 compound heterozygotes including c.250T>C (p.Cys84Arg) (9.5% prevalence) (PMID:34694653). In Lithuania, 8 families harbored biallelic variants, predominantly p.Arg37Pro homozygotes and a novel c.299A>G (p.Glu100Gly) found in 3 pedigrees, supporting a shared founder haplotype (PMID:36242072).

Although formal segregation counts are sparse, co-segregation within sibships and recurrence of founder alleles across >20 unrelated families underpin an autosomal recessive inheritance without notable conflicting reports.

Functional characterization supports a loss-of-function mechanism: the p.Glu100Gly variant yields a catalytically active yet unstable HINT1 protein in patient cells, phenocopying complete loss (PMID:36242072). Biochemical assays reveal HINT1 as a zinc- and calmodulin-regulated SUMO protease; neuropathy-associated mutants exhibit impaired sumoylase activity on regulatory substrates (PMID:31088288).

Mechanistic studies further demonstrate that Hint1 deficiency impairs ATM activation and γ-H2AX acetylation following DNA damage, delaying repair and contributing to neuronal vulnerability (PMID:18852295). This nexus between DNA damage response and peripheral nerve integrity consolidates haploinsufficiency-like pathogenicity.

Integration of robust genetic series, recurrent founder alleles, and concordant functional data across multiple models establishes a Definitive gene–disease association for HINT1 in ARAN-NM. Key take-home: inclusion of HINT1 in CMT diagnostic panels enables accurate molecular diagnosis and informs future therapeutic strategies.

References

• Nature Genetics • 2012 • Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. PMID:22961002
• Journal of the Peripheral Nervous System : JPNS • 2021 • HINT1-related neuropathy in Greek patients with Charcot-Marie-Tooth disease. PMID:34694653
• Orphanet Journal of Rare Diseases • 2022 • HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling. PMID:36242072
• Antioxidants & Redox Signaling • 2019 • The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease. PMID:31088288
• The Journal of Cell Biology • 2008 • The HINT1 tumor suppressor regulates both gamma-H2AX and ATM in response to DNA damage. PMID:18852295

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