Relationships of GDAP1 Mutations to Disease Phenotype and Mechanisms of Therapeutic Action of Oxidative Metabolism Activators in a Patient with Charcot–Marie–Tooth Neuropathy Type 2K

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Nadejda R. Borisova¹, Alina A. Emelyanova², Olga N. Solovjeva³, Natalia V. Balashova^4,5, Olga P. Sidorova⁴, and Victoria I. Bunik^1,2,3,a*

¹Sechenov University, 119048 Moscow, Russia

²Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

³Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

⁴Faculty of Advanced Medicine, Vladimirsky Moscow Regional Research and Clinical Institute, 129110 Moscow, Russia

⁵Faculty of Continuing Medical Education, RUDN Medical Institute, 117198 Moscow, Russia

^* To whom correspondence should be addressed.

Received: July 6, 2025; Revised: October 5, 2025; Accepted: October 18, 2025

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The development of personalized medicine, including the treatment of hereditary diseases, requires translation of advances in biochemistry into medical practice. Our work is dedicated to solving this problem in a clinical case of hereditary Charcot–Marie–Tooth neuropathy type 2K (CMT2K), induced by the compound heterozygous mutations in the GDAP1 gene leading to the protein variants with the most common in Europe substitution L239F (inherited from the father) and previously uncharacterized substitution A175P (inherited from the mother). The ganglioside-induced differentiation-associated protein 1 (GDAP1) encoded by the GDAP1 gene is located in the outer mitochondrial membrane and belongs to the glutathione S-transferase superfamily. Our structure-function analysis of GDAP1 shows that dimerization of its monomers with either L239F or A175P substitutions, along with the half-of-the-sites reactivity of GDAP1 to hydrophobic ligands, may synergistically impair the binding due to the double amino acid substitution in one of the active sites. This mechanism explains the early disease onset and progress in the child, whose parents heterozygous by each of the mutations are asymptomatic. Published phenotypes of amino acid substitutions in the GDAP1 region comprising the binding site for hydrophobic compounds are analyzed, including phenotypes of the homozygous L239F substitution and its compound heterozygous combinations with other substitutions in this region. Based on the found association of these substitutions with the axonal form of Charcot–Marie–Tooth disease (CMT) and disturbances in the NAD⁺- and thiamine diphosphate (ThDP)-dependent mitochondrial metabolism, the therapeutic effect of nicotinamide riboside (NR) and thiamine (precursors of NAD⁺ and ThDP, respectively) in the patient is studied. Oral administration of thiamine and NR increases levels of ThDP and NAD⁺ in the patient’s blood, improves the hand grip strength, and, after a long-term administration, normalizes the ThDP-dependent metabolism. After the therapy, the diseased-altered activities of transketolase (TKT) and its apo-form, as well as the relationship between the activity of the TKT holoenzyme and ThDP and NAD⁺ levels in the patient’s blood, approach those of healthy women. Our results demonstrate the therapeutic potential of thiamine and NR in correcting metabolic dysregulation in CMT caused by mutations in GDAP1, suggesting the underlying molecular mechanisms. Genetic diagnostics and biochemical characterization of mechanisms involved in the pathogenicity of mutations in clinically asymptomatic patients or patients at the early CMT stages may increase the efficacy of therapy, as it is easier to protect from the accumulating metabolic damage than to reverse it.

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KEY WORDS: GDAP1, pyruvate dehydrogenase kinase, compound heterozygous mutations, muscle strength, Charcot–Marie–Tooth neuropathy, nicotinamide riboside, thiamine, transketolase, tricarboxylic acid cycle

DOI: 10.1134/S0006297925601911

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