What a frameshift mutation means in terms of disease depends very much on where the mutation occurs. 

Example 1: If a mutation occurs early on in the sequence of the protein, then little or no of the original protein is generated. This would lead to a loss of activity.

Example 2: If a mutation occurs near the end of the protein sequence which results in a slightly earlier stop codon, then most of the amino acids required are present and somewhat normal folding can occur. This could lead to a reduction in activity, but some normal function can still be carried out.

Example 3: If a mutation occurs near the end of the protein sequence but results in a gain of amino acids which disrupt the normal folding of the protein this could prevent it from interacting with other proteins required to carry out its normal function. This would lead to a loss of activity.

What a nonsense mutation means in terms of disease depends very much on where the mutation occurs. 

Example 1: If a mutation occurs early on in the sequence of the protein, then little or no amino acids are generated. In this case, there is usually no functional protein produced. This would lead to a loss of activity.

Example 2: If a mutation occurs near the end of the protein sequence, then most of the amino acids required are present and somewhat normal folding can occur. This could lead to a reduction in activity, but some normal function can still be carried out.

Example 3: If a mutation occurs near the end of the protein sequence but results in the loss of a crucial part of the protein this could prevent it from interacting with other proteins required to carry out its normal function. This would lead to a loss of activity.

What a missense mutation means in terms of disease depends very much on where the mutation occurs. 

Example 1: If a mutation occurs in an amino acid that is vital for how the protein folds, a missense mutation may completely disrupt the shape of the protein, preventing it from interacting with other proteins required to carry out its normal function. This would lead to a loss of activity.

Example 2: If a mutation occurs in an amino acid that only slightly changes how a protein folds, therefore retaining some though not all of its ability to interact with other proteins. This would lead to a reduction in activity, but some normal function can still be carried out.

Click on the links below to find out more about each type of mutation:

• Missense mutations
• Nonsense mutations
• Frameshift mutations

The key finding of this paper: It is believed that Warburg Micro syndrome (WARBM) and Martsolf syndrome are not separate disorders. Rather they are on a spectrum that reflects the extent to which an individual’s genetic makeup disrupts the function of a protein called RAB18. Changes in the genes RAB3GAP1, RAB3GAP2 and RAB18 that result in complete loss-of-function of the encoded protein result in WARBM. Whereas, less damaging changes in these same genes, that allow some functional protein to be made result in the less severe Martsolf syndrome. 

Warburg Micro syndrome (WARBM) and Martsolf syndrome share similar symptoms and underlying genetic causes. Both syndromes are passed from parent to child in an autosomal recessive manner. This means that an affected child must have two copies (one from each parent) of a gene with a disease-causing change. Of the two syndromes WARBM presents with more severe symptoms. Affected children present with a range of symptoms including significant  visual impairment, severe developmental delay and progressive muscle weakness. In comparison, Martsolf syndrome presents with less severe symptoms. Generally, patients experience less visual impairment, less severe intellectual disability and muscle weakness in the lower limbs only. Despite the difference in the severity of symptoms between the two syndromes, disease-causing genetic changes in the same genes are responsible for both syndromes.

The authors of this report created a publicly available online database to record all of the known disease-causing genetic changes in the genes RAB18, RAB3GAP1 and RAB3GAP2 that result in WARBM and Martsolf syndrome as of 2013. The database details the specific disease-causing genetic change in each family and the clinical symptoms experienced. As of 2013 a total of 153 families were investigated and disease-causing genetic changes were found in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases and in RAB18 in 5% of cases. Therefore, disease-causing genetic changes were most commonly found to occur in RAB3GAP1. 

Genes (such as RAB3GAP1) are sections of DNA (or Deoxyribonucleic Acid) that contain the instructions to make specific proteins. DNA is made up of a simple alphabet of just 4 letters: A, C, G and T. How these letters are arranged in sequences determines the protein made by the cell. However, if there is a change in the sequence of letters this can affect how the sequence is read by the cell and in turn affect the production of the protein (Figure 1). These changes can result in a ‘loss-of-function’ which prevents the normal protein product being made or makes the protein inactive.        

     
Figure 1: The DNA sequence to make the protein RAB3GAP1 has change in the sequence of the letters. The change of a ‘C’ to an ‘A’ affects how the cell reads the sequence and the production of the protein stops prematurely. Figure made with BioRender. 

Disease causing changes in any of RAB18, RAB3GAP1 or RAB3GAP2 can result WARBM or Martsolf Syndrome. However, children display similar clinical features regardless of which gene the disease-causing change is in. It is not possible to determine which gene contains the disease-causing change based on clinical features alone. Therefore, which gene contains the disease-causing change does not determine the severity of disease. Rather the location of the change in the DNA sequence is important in determining disease severity. If a change in the sequence occurs in a region of the gene that is very important for protein function it is likely to result in more severe disease. Similarly, if a change in the sequence results in very little functional protein being produced this is also likely to result in more severe disease. In contrast, if a change in the sequence still allows some functional protein to be produced it is likely to result in less severe disease. 

This report describes some of the specific disease-causing changes and clinical features seen in families with WARBM and Martsolf syndrome. In this report two newly described disease-causing changes in the sequence that makes the RAB3GAP1 protein were identified in patients. These changes were single letter changes in the sequence that produces RAB3GAP1 protein. Computational tools predicted these changes to be “possibly damaging” and “disease causing” significantly affecting the function of the RAB3GAP1 protein. These disease-causing genetic changes are believed to result in loss-of-function of the RAB3GAP1 protein and patients symptoms were described as being consistent with the more severe symptoms seen in WARBM syndrome. 

The case of two families that have a one letter change in the sequence that makes the protein RAB3GAP2 is also detailed in this report. The affected patients have milder symptoms typically seen in Martsolf syndrome. The investigators believe that the disease-causing change in the RAB3GAP2 sequence disrupts the function of the RAB3GAP2 protein but does not result in complete loss of RAB3GAP2 protein function. Therefore, as there is some protein function and not a complete loss of protein function a less severe disease presentation is seen. 

Interestingly, this report also details the case of a family that presents with WARBM that has another type of change in the RAB3GAP1 protein sequence. Specifically, this family has an insertion of extra letters in the sequence of the RAB3GAP1 protein sequence. Notably, this change in the sequence occurs towards the very end of the RAB3GAP1 sequence. Despite this change occurring so late in the protein sequence it is suggested that the change has occurred in a section of the sequence that could be essential for protein function or the stability of the protein. 

In summary, it is believed that WARBM syndrome and Martsolf syndrome are not separate disorders. Rather they are on a spectrum that reflects the extent to which an individual’s genetic makeup disrupts the function of a protein called RAB18 in their body (Figure 2). Changes in the genes RAB3GAP1, RAB3GAP2 and RAB18 that result in complete loss-of-function of the protein result in WARBM. Whereas, less damaging changes in these same genes, that allow some functional protein to be made result in the less severe Martsolf syndrome. 

Figure 2. WARBM syndrome and Martsolf syndrome are both on a spectrum of how severe an affected patient’s deficiency of RAB18 is. Figure made with BioRender.