WHAT IS CNNM2-ASSOCIATED DISEASE?

If you or a loved one has been diagnosed with CNNM2-associated disease, you will have many questions you need answers for and concerns to be addressed. We have included some information that may help answer your questions about the disease here. If you can’t find an answer for your question, contact us at CNNM2patients@jain-foundation.org.

FAQ: Range of Symptoms, Prognosis, & Inheritance

CNNM2-associated disease is caused by a genetic mutation in the CNNM2 gene. In most cases it is a dominant condition, so people with this disease have at least one non-functional gene copy. There are many different mutations that disrupt the function of the CNNM2 gene product: some children will have inherited the disease from a parent who shares the disease, while in other children a mutation will have emerged de novo, meaning the disease arose spontaneously in the egg or sperm.

The range of reported experiences and symptoms in CNNM2-associated disease is highly diverse. Some children may experience milestones at the same time as their peers. Other children’s mutations in CNNM2 may lead to developmental delay. Speech may be particularly delayed in these cases, and the child may require extra support for the transition to school and beyond.

One clinical study indicates seizures reduced or stopped with age in one group of patients, but this should be taken as purely anecdotal. There are no indications that the disease has any negative consequences for lifespan.

Because CNNM2-associated disease is caused by misregulated transport magnesium throughout the body, many people with this condition will take oral magnesium supplements. People who have other symptoms such as seizures or migraines should speak with their doctor and devise a specific treatment plan to address those symptoms.

Because CNNM2-associated disease is so rare (with an estimated population frequency of less than one in a million), our understanding of the range of symptoms is likely incomplete. However, we know that all people with CNNM2-associated disease suffer from low levels of magnesium in the blood, or hypomagnesemia.

Different people will experience different other symptoms. These might include:

  • Epilepsy and seizures
  • Developmental delay including pronounced speech delay
  • Migraines
  • Trouble sleeping
Proteins, DNA and Mutations

Proteins are large molecules that make up the structure of cells and help them do their particular function.  There are two basic types of proteins. Some form the structure of cells – you can think of these proteins as building blocks that are put together to make cells. Others carry out certain functions within the cell – you can think of these proteins as small machines inside your body. The dysferlin protein is one of these machines, and scientists think that dysferlin has many jobs, such as fixing holes in the membrane (the outer wall) of the cell, moving things around in the cell and regulating the amount of calcium, which is important for muscle function. Which of these functions or combination of functions are the most relevant to the underlying pathophysiology of dysferlinopathy has yet to be determined.

All proteins, both building blocks and machines, are actually long chains that are folded up into three-dimensional shapes. Each protein chain is made up of connected links called amino acids. There are 20 different kinds of amino acids, each with a slightly different shape. The different kinds of amino acids are strung together in a specific sequence to form a protein chain. The exact sequence of these amino acids in the protein is very important for the protein to fold up correctly and to carry out its proper function in the cell.

CNNM2 refers both to the gene of the same name, and to its protein product. It is part of the closely-related CNNM protein family, originally named ACDP for “ancient conserved domain protein”. All four members of this protein family seem to function as magnesium transporters in different parts of the body.

DNA (deoxyribonucleic acid) is the information storage system of the body. DNA is a code that contains instructions telling the cell how to make all of its proteins. There is a separate DNA code (a gene) corresponding to each protein that is made by the cell. For example, instructions for how to make the CNNM2 protein are encoded in DNA in the CNNM2 gene.

Like proteins, DNA molecules are also long chains. But DNA chains don’t act as machines, they just store instructions for making the protein chains. Each protein is a chain of amino acids, and each DNA molecule is a chain of connected links called nucleotides. There are four different nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C). Each set of three nucleotides is code for a specific amino acid. For example, if the DNA has the nucleotides adenine, then thymine, then guanine in a row (ATG), that is code for an amino acid called Methionine.

The DNA that makes up the gene that encodes a protein sometimes has mistakes, called mutations, which cause defects in proteins. For example, if there are mutations in the CNNM2 gene, then the CNNM2 protein will not be made correctly. Each individual with CNNM2-associated disease has at least one such mutation, which can be found by gene mutation analysis (genetic sequencing). Different mutation types are described below:

  • A MISSENSE mutation causes just one of the amino acids in the protein to be wrong.
    This mutation is a mistake in one DNA nucleotide in a gene. That one nucleotide is part of a set of three nucleotides that code for a specific amino acid. When a ribosome reads this particular set of three nucleotides, one of them is wrong and the ribosome selects the wrong amino acid for the protein. Missense mutations can range from very mild to severe, depending on where in the protein the affected amino acid is located and how important the affected amino acid is to the protein’s function or stability of the protein.
  • A SPLICE-SITE mutation causes a problem with the DNA instructions.
    This can be caused by a sizeable portion of the DNA instructions for a particular protein being deleted or the adding of instructions that shouldn’t be there.  The end result of either scenario is that the DNA instructions are incorrect which results in the wrong amino acid sequence or in the protein not being made at all.  Splice-site mutations can range from moderate to severe, depending on how much the mutation alters the DNA instructions for the protein. This is a severe defect because much of the protein is missing so the protein cannot function correctly, and the non-functional protein will likely be degraded leading to the complete absence of the protein.
  • A FRAMESHIFT mutation causes all of the amino acids in the protein, after a certain point, to be wrong.
    This mutation is an insertion or deletion of one or more nucleotides in the DNA. Because a ribosome makes the protein by reading sets of three nucleotides, inserting or deleting a nucleotide means that the ribosome can no longer correctly group the sets of three. Every set of three after the insertion/deletion is incorrectly grouped, so the ribosomes pick the wrong amino acid for every set of three after this point in the protein. By analogy, imagine that each word in a sentence stole the first letter of the next word (THE RED CAR would become HER EDC AR) – the words would no longer be read correctly.
  • A NONSENSE or STOP mutation causes the protein chain to stop prematurely.
    This mutation is a mistake in the DNA code that tells the ribosomes to stop attaching new amino acids to the protein while the protein is still incomplete. The ribosomes stop too early and never even make part of the protein.

Mutations in the CNNM2 gene result in less functional CNNM2 protein present in cells. Because CNNM2 functions as a magnesium transporter, mutations in CNNM2 result in disruptions to the supply of magnesium throughout the body. This manifests in different ways depending on the individual.

Magnesium is an important electrolyte used by the body in a wide array of cellular processes, and is critical for life. Most people get all the magnesium they need from their diet. People with mutations in CNNM2 seem to have trouble keeping magnesium in their body and circulating it to all the organs that need it. In the kidney, CNNM2 mutations lead to magnesium wasting and electrolyte imbalances in the blood and urine. In the brain, a lack of magnesium can make someone prone to seizures. Magnesium is also involved in some hormonal signals related to metabolism and appetite.