Multiple Ways Gene Now Linked to CMT Type 2, DHTKD1, Causes Disease Traced in Study

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Mutations in DHTKD1, a recently discovered cause of a Charcot-Marie-Tooth (CMT) type 2 subtype, can lead to the disease through a mechanism involving problems with cellular metabolism, insulin release, and overproduction of a myelin protein, researchers report.

The study titled “DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice” was published in the journal Molecular and Cellular Biology.

Charcot-Marie-Tooth (CMT) disease represents a set of hereditary neuropathies characterized by defects in the function of peripheral nerves — the nerves that control motor (movement) and sensory (taste, smell, or touch) functions.

It is caused by different gene mutations that lead to degeneration of either nerve fibers or their surrounding myelin sheath, a thin insulating and protective layer needed for communication between nerve cells.

Clinically, the most common disease forms are CMT type 1 and CMT type 2, both characterized by muscle weakness and wasting (atrophy), and reduced sensation (touch, heat, cold), particularly in the extremities, such as the feet, lower legs, hands, and forearms.

There are several disease subtypes for both CMT1 and CMT2, according to the gene that is mutated.

Researchers identified a new mutation in 2012 that caused CMT type 2Q, found in several members of a Chinese family. The mutation was located in a gene whose association with CMT was ignored until then, called DHTKD1.

Now, work by this same research team provides new insights into the molecular mechanisms associated with the mutation and disease onset.

DHTKD1 provides instructions for cells to produce a component of an enzyme called 2-oxoglutarate-dehydrogenase-complex-like, important for the breakdown of amino acids, the building blocks of proteins. This enzyme works on special cell compartments called mitochondria, which are the main energy production centers in cells and key players in metabolism.

People with mutations that cause a loss of DHTKD1 often develop a type of inborn metabolic disorder called alpha -aminoadipic and alpha -ketoadipic aciduria (AMOXAD), which can manifest as several neurological abnormalities, motor developmental delay, and low muscle tone.

To further understand why DHTKD1 loss leads to disease, including to CMT2, researchers analyzed the molecular pathways affected in mouse models deficient for the DHTKD1 gene.

First, they confirmed that DHTKD1-deficient animals mimic the major symptoms of CMT2 in humans: progressive weakness and muscle wasting in the extremities of limbs, sensory problems, and slower conduction of nerve electrical impulses.

Moreover, DHTKD1 deficiency was also seen to cause severe abnormalities in cells’ metabolism (chemical processes essential to cell life), and an excessive accumulation of two metabolic products, called 2-KAA and 2-AAA.

Overproduction of these two molecules stimulated the pancreas to release more insulin — a major hormone that controls sugar uptake by cells for energy production. In turn, a excess insulin induced the production of a protein called myelin protein zero (MPZ), the principal component of myelin, leading to nerve cell degeneration.

Finally, the disease-causing role of 2-AAA was confirmed when mice fed 2-AAA began to exhibit CMT2-like symptoms, including motor problems and evidence of damage to myelin and nerve fibers.

The findings provide a molecular explanation linking DHTKD1 deficiency to 2-KAA and 2-AAA excess, insulin imbalance, and myelin and nerve cell damage.

They show “an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies,” the researchers concluded.