Chinese Family’s Rare MPZ Mutation Linked to Intermediate CMT Form

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A rare mutation in the myelin protein zero (MPZ) gene leads to higher-than-normal levels of the MPZ protein and is associated with an intermediate form of Charcot-Marie-Tooth disease (CMT), a study in China shows.

Notably, the mutation, affecting four generations of a Chinese family, was present in only one MPZ gene copy, consistent with what has been previously reported for other CMT-related MPZ mutations.

These findings add to the number of previous studies highlighting an association between MPZ mutations and different forms of CMT, and provide further insights into the potential mechanisms behind the damaging effects of this particular mutation, the researchers noted.

The study, “MPZ gene variant site in Chinese patients with Charcot–Marie–Tooth disease,” was published in the journal Molecular Genetics and Genomic Medicine.

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CMT is a group of inherited progressive disorders of the peripheral nervous system, which controls movement and sensation in the limbs. It is mainly divided into “demyelinating CMT,” also known as CMT type 1 (CMT1), and “axonal CMT,” or CMT type 2 (CMT2).

Demyelinating CMT is characterized by progressive demyelination, or the loss of myelin, which is the protective sheath around axons — nerve fibers that carry signals to the next nerve or muscle cell. Axonal CMT is characterized by the degeneration of these axons.

More than 200 different MPZ mutations have been associated with several CMT subtypes — such as CMT1, CMT2, and CMT3, also called Dejerine-Sottas syndrome — and a wide range of clinical manifestations.

The MPZ gene provides instruction to produce a protein of the same name that is abundant within myelin and works as an adhesion molecule, mediating myelin compaction around axons of the peripheral nervous system.

Still, few studies have conducted functional analysis on MPZ mutations to understand their impact on the MPZ protein and subsequently on myelin compaction and axonal health.

A research team now described a rare CMT-associated MPZ mutation (p.Lys130Arg) in four generations of a Chinese family and its effects on MPZ protein.

The first relative observed was a 28-year-old woman with proprioceptive sensation disturbances in both her upper and lower limbs, symmetrical muscle wasting in the hands, and steppage gait.

Proprioception is the sense of self-movement and body position; in steppage gait, a person is unable to lift the foot while walking due to muscle weakness.

Nerve studies showed both demyelination and severe axonal damage, suggesting an intermediate CMT form.

Genetic testing identified the mutation in one of her two MPZ gene copies. This mutation, comprising a single nucleotide change in the gene’s sequence, results in an amino acid switch in the resulting MPZ protein. Nucleotides are the building blocks of DNA, while amino acids are proteins’ building blocks.

Among the 64 members of her family within four generations, 17 (nine males and eight females) had different clinical symptoms, and 41 had no signs of CMT. (Not all family members were evaluated.)

Researchers collected blood samples from the woman and 11 other affected relatives (average age, 41.8) and 43 healthy volunteers unrelated to the family (average age, 29).

They found that the affected woman had no mutations in other known CMT-related genes, and that the p.Lys130Arg mutation was present in her and her affected relatives, and absent in healthy volunteers.

The 12 affected individuals (seven females and five males) had a disease onset at about age 6 — average age of 6.3 for females and 6.5 for males, supporting no sex differences in this type of CMT.

In all of those with available data, symptoms began in the upper limbs, with signs of proprioceptive sensation impairment, and gradually worsened with increasing age, involving also the lower limbs.

Patients showed distinct levels of symmetrical muscular wasting and most showed steppage gait with different degrees of numbness in the limbs, most commonly the muscles in the feet.

Similar to other CMT-related MPZ mutations, p.Lys130Arg was inherited in an autosomal dominant manner, meaning that a person had to inherit only one mutated copy to develop the disease.

Based on these data, the mutation is likely “a rare variant that is associated with coexisting demyelination and axonal involvement; intermediate CMT, with accompanying [autosomal dominant] inheritance,” the researchers wrote.

The team then analyzed the effects of the MPZ mutation on the gene’s activity and MPZ protein by analyzing blood samples from the 12 affected family members and 12 randomly selected controls.

They found that affected individuals had significantly higher levels of MPZ’s messenger RNA, the molecule derived from DNA that guides protein production, and MPZ protein than healthy controls.

Patients with more complicated clinical symptoms and greater organ involvement also had higher blood MPZ levels, suggesting that MPZ levels were associated with disease severity and progression.

Moreover, the blood levels of PKC, an enzyme that activates MPZ’s adhesion function in myelin compaction, were significantly increased in affected individuals relative to controls, suggesting that MPZ may also be overly activated in these patients.

“We will further confirm the reliability of this conclusion in future experiments,” the researchers wrote.

In the future, detecting MPZ levels in blood samples may help “provide a preliminary reference for the early-stage clinical diagnosis of CMT,” which can be subsequently confirmed by clinical symptoms and family history, the researchers wrote.

They also noted that this testing may be applicable for prenatal and childhood early screening and diagnosis of CMT associated with MPZ mutations.