Submission Details

PDK3 was first reported in relation to X linked dominant Charcot Marie Tooth disease 6 (CMTX6) in 2013 in a large Australian family (Kennerson et al., PMID: 23297365). Linkage analysis mapped the locus to Xp22.11, and further haplotype analysis and exome sequencing identified a missense variant p.R158H in PDK3 gene segregating in all affected family members. Male patients presented with foot deformity, gait abnormalities, hand tremor, absent ankle reflexes, distal lower limb weakness, sensory abnormalities, and motor developmental delay. Carrier females were asymptomatic or mildly affected. Disease was progressive with childhood onset of a predominantly axonal motor and sensory neuropathy. The same missense variant was later reported in an unrelated Korean family, affected individuals presented with similar clinical manifestations as those of the Australian family (Kennerson et al., PMID: 26801680). The variant p.R158H seems to occur on a different haplotype when compared with the original Australian CMTX6 family, excluding a common founder. Other missense variants were reported in the literature, but since pathogenicity was only confirmed for the recurrent missense variant p.R158H, they were not included in this curation.

PDK3 gene comprises 12 exons and encodes for pyruvate dehydrogenase kinase 3, a protein residing in the mitochondrial matrix. PDK3 is one of the four isoenzymes negatively regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation of its catalytic subunit E1. PDK3 is expressed in the human spinal cord, fetal and adult brain, as well as in skeletal muscle. Expression in the brain was also shown in mouse and rat tissues.

Primary fibroblasts cultured from CMTX6 patients showed hyperphosphorylation of E1 at selected serine residues and subsequent reduction of PDC activity. The variant p.R158H had, however, no effect on the level of PKD3 expression in fibroblasts (PMID: 27388934, PMID: 32504000). Patient fibroblasts showed increased lactate, decreased ATP, and alteration of the mitochondrial network (PMID: 27388934). Furthermore, E1 hyperphosphorylation was maintained in patient derived iPSC cells as well as patient derived motor neurons. Phosphorylation was reverted by either gene editing of the p.R158H variant or pharmacological inhibition (PMID: 32504000).

This gene-disease relationship is also supported by C. elegans knock-in and overexpression models. Both showed reduced body width, defective stress response to paraquat induced oxidative stress, axon-associated synaptic transmission deficits, and reduced ATP levels; recapitulating the phenotype observed in patient fibroblasts and iPSC-derived motor neurons (PMID: 34387338).

In summary, there is definitive evidence supporting the relationship between PDK3 and X linked dominant Charcot-Marie-Tooth disease 6. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.