Researchers have identified MCM3AP as a gene involved in the development of a childhood-onset version of the neurological disorder Charcot-Marie-Tooth disease.
The study, “MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability,” was published in the journal Brain.
Charcot-Marie-Tooth disease (CMT) is a group of hereditary neuropathies, or diseases affecting the nerves. They are divided into three categories, depending on nerve conduction, or how fast electrical signals move through nerves. The categories are demyelinating CMT (CMT1), axonal CMT (CMT2) and intermediate CMT.
There are many types of CMTs. A type known as autosomal recessive CMT is generally more severe than others and appears in childhood. Autosomal recessive refers to the pattern of inheritance: Two copies of an abnormal gene must be present for the disease to develop.
More than 70 genes are known to cause CMT. Many people with the disease do not know which genes cause theirs because scientists have yet to discover many of the genes involved in CMT.
University of Helsinki researchers studied nine patients from five families to see if they could find genes that cause CMT. They used whole exome sequencing, which sequences all of the genes that a person is expressing, or producing proteins with. The families were from ethnic Finnish, Australian, Canadian, Dutch and Turkish backgrounds.
The patients had both neurological and non-neurological symptoms. Nerve conduction studies showed that patients from four of the five families had axonal neuropathy, or CMT affecting a neuron component called an axon. The disease of the Turkish-descended family was too advanced to be tested for nerve conduction.
Most of the patients had impaired cognition. Seven had mild to moderate intellectual disability and two a learning disability or delayed speech development.
Sequencing showed that the patients had MCM3AP gene mutations, with different mutations correlating with different characteristics in the families.
The MCM3AP gene produces the GANP protein, whose full scientific name is germinal center associated nuclear protein. Scientists have yet to determine the protein’s function, but they know it plays a role in transporting mRNA from the nucleus to the cytoplasm of cells. Cytoplasm is where proteins are created.
Researchers hypothesized that the families’ MCM3AP variations would either decrease GANP levels or affect its function by changing its structure. Analysis of patients’ skin cells showed that MCM3AP variations were associated with a significant decrease in GANP levels. Researchers also demonstrated that GANP is present in neurons.
Taken together, the results indicated that MCM3AP variations are associated with both nerve disease and intellectual disability in CMT patients. “The identification of MCM3AP variants in affected individuals from multiple centers establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability,” the authors wrote.