Rare POLR3B Mutation Again Linked to Early-onset CMT Type 1

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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In rare cases, de novo or non-inherited mutations in one copy of the POLR3B gene can cause an early-onset demyelinating form of Charcot-Marie-Tooth disease (CMT), according to a study from Japan involving more than 800 CMT patients.

While mutations in both POLR3B gene copies have been shown to cause a rare neurodevelopmental disease called hypomyelinating leukodystrophy, this is only the third report of a link between de novo mutations in one of the gene’s copies and CMT.

These findings highlight that while CMT-causing POLR3B mutations are rare, the POLR3B gene should be included in the panel of CMT-associated genes for genetic screening, particularly in people presenting early-onset demyelinating disease, the researchers noted.

The study, “Novel de novo POLR3B mutations responsible for demyelinating Charcot–Marie–Tooth disease in Japan,” was published in the journal Annals of Clinical and Translational Neurology.

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CMT is a group of inherited disorders of the peripheral nervous system that controls movement and sensation in the limbs. It is mainly divided into “demyelinating CMT,” also known as CMT type 1, and “axonal CMT” or CMT type 2.

Demyelinating CMT is characterized by progressive demyelination, or loss of myelin, which is the protective sheath around nerve fibers, or axons. Axonal CMT is identified by nerve fiber degeneration.

This differentiation is based on results of nerve conduction velocity tests, which measure how quickly electrical impulses move along a nerve cell. Markedly slow velocities reflect myelin damage, while higher velocities suggest axonal damage.

Mutations in more than 100 genes have been shown to cause the various types of CMT.

Two previous studies reported a link between a de novo mutation in one POLR3B gene copy (c.3137G>A) and an early-onset demyelinating form of CMT. The first described the case of an 11-year-old boy in Canada, while the second referred to a 19-year-old man in China.

De novo mutations are those that, instead of being inherited from parents, develop for the first time in the affected person. The POLR3B gene provides instructions to produce a subunit of Polymerase 3 (Pol3), an enzyme involved in the regulation of gene activity and protein production.

These cases highlighted the distinct consequences of POLR3B mutations when present in one of  a person’s two gene copies (one inherited from each biological parent), as double POLR3B mutations are a well-established cause of a rare hypomyelinating leukodystrophy characterized by hypomyelination, or abnormally low amount of myelination, missing teeth, and reproductive problems.

A team of researchers in Japan described two additional cases of early-onset demyelinating CMT caused by de novo POLR3B mutations.

They re-analyzed whole-exome sequencing (WES) data from 804 people in Japan with demyelinating CMT and no known CMT-causing mutations, searching for the presence of POLR3B mutations.

WES looks at all of a person’s exons, the sections in DNA that provide instructions for making proteins. Of note, genes are comprised of exons interspaced with non-coding regions called introns.

Results showed that two women (0.2%) carried previously unknown POLR3B mutations (c.1405C>T and c.1469G>A). Since these mutations were not present in their parents, they were classified as de novo.

Both variants were absent from public and in-house control databases, further highlighting their rarity. Computational analyses using multiple tools suggested that these mutations had damaging effects on the resulting Pol3 enzyme.

The first woman died at the age of 54 due to respiratory failure. Neither woman had a family history of conditions associated with peripheral nervous system damage.

In both cases, delayed motor milestones were noted before or about 2 years of age, and they were diagnosed with CMT between the ages of 8 and 10. The first woman needed to use a wheelchair since age 16, while the second, at age 26, was still able to walk independently.

Both women developed marked muscle weakness and wasting in the hands and feet, sensory impairment, and lost their tendon reflexes. Slow nerve conduction velocities were observed in both patients, suggesting a demyelinating form of CMT.

No intellectual disability, ataxia (loss of movement control), spasticity (stiff or tight muscles), or seizures were reported.

Notably, an MRI given the first patient as an adult showed mild shrinkage in the spinal cord and the cerebellum, a brain region involved in motor and balance control. This highlighted damage in the central nervous system (brain and spinal cord).

These women showed similar features to the two previously reported male cases, further emphasizing a link between de novo mutations in one POLR3B’s copy with early-onset demyelinating CMT.

“Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT,” the researchers wrote.