HK1 – Charcot-Marie-Tooth Disease Type 4G

Hexokinase 1 (HK1) is associated with autosomal recessive Charcot-Marie-Tooth disease type 4G (CMT4G), a demyelinating sensorimotor neuropathy characterized by progressive distal limb weakness and sensory loss (HK1; Charcot-Marie-Tooth Disease Type 4G).

CMT4G was first identified in the Balkan Roma population as a childhood-onset myelinopathy linked to two homozygous founder variants in the 5′ untranslated region (UTR) of HK1 (g.9712G>C and g.11027G>A) that segregate with disease in multiple gypsy families (PMID:19536174).

Affected individuals typically present in the first decade with distal lower limb weakness, followed by upper limb involvement and prominent distal sensory impairment, reflecting a chronic demyelinating sensorimotor polyneuropathy phenotype.

Whole-exome sequencing in an Iranian CMT4G patient revealed a homozygous nonsense variant c.19C>T (p.Arg7Ter), marking the first report of this coding change outside European Roma and expanding the mutational spectrum of HK1-related CMT (PMID:38301092).

The same p.Arg7Ter variant was subsequently identified in an unrelated Pakistani patient, suggesting a possible prevalence of this allele in Middle Eastern populations (PMID:38301092).

Functional assays demonstrate that CMT4G-associated HK1 5′UTR mutations disrupt HK1 binding to the voltage-dependent anion channel 1 (VDAC1), leading to impaired mitochondrial calcium buffering in patient cells, whereas expression of wild-type HK1 or an N-terminal peptide restores VDAC1 interaction and calcium handling in vitro (PMID:38673950).

Taken together, genetic and experimental data robustly support a loss-of-normal HK1–VDAC1 interaction as the pathogenic mechanism in CMT4G. Key take-home: identification of HK1 5′UTR or truncating variants enables molecular diagnosis and informs therapeutic strategies targeting mitochondrial calcium homeostasis.

References

• European Journal of Human Genetics • 2009 • A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR). PMID:19536174
• Archives of Iranian Medicine • 2023 • Expanding the Molecular Spectrum of HK1-Related Charcot-Marie-Tooth Disease, Type 4G; the First Report in Iran. PMID:38301092
• International Journal of Molecular Sciences • 2024 • The Hexokinase 1 5′-UTR Mutation in Charcot-Marie-Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering. PMID:38673950

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