The discovery of serum proteins that are specific to FAC (familial amyloid cardiomyopathy) and FAP (familial amyloid polyneuropathy) may aid in the diagnosis and prognosis of these diseases, new research shows.
The study, “Serum Proteomic Variability Associated with Clinical Phenotype in Familial Transthyretin Amyloidosis (ATTRm),” was published in the Journal of Proteome Research.
Mutations in the TTR (transthyretin) gene can cause the TTR protein to be misfolded and aggregated, which leads to deposits of amyloid fibrils into heart and nerve tissues. Collectively, this group of diseases is called ATTR (TTR-associated amyloidosis). Depending on the clinical phenotype, these diseases can either be classified as FAC or FAP.
It is hard to diagnose FAC and FAP because there are no definite biomarkers of the disease. No reliable markers of progression exist, and treatment options are lacking.
Therefore, it is crucial for researchers to determine potential sensitive and specific indicators to improve doctors’ recognition of the disease as well as measure progression and response to treatment.
Researchers conducted a proteomic (protein-focused) analysis of ATTR, both for FAC and FAP, with control samples to assess which proteins are indicative of which disease. They used a powerful technique called multiple-reaction monitoring mass spectrometry (MRM-MS), which can be used to profile proteins from patient samples.
They studied 192 serum proteins and compared the levels of each protein from both healthy samples and ATTR samples.
Results showed there were significant differences in 107 of the 192 proteins. TTR levels were significantly lower in FAC, but not in FAP.
Also, when comparing FAC to FAP, significant differences were found in levels, interactions, and functions of many proteins that were identified as being unique to each disease. Researchers conducted clustering analysis on serum proteins from FAC and FAP samples, which is the categorization of all proteins according to their characteristics including location, function, sequence type, and interactions.
They discovered that proteins located in the extracellular region and involved in signaling were common to both FAP and FAC. Proteins with disulfide bonds were unique to FAC samples.
However, proteins that were secreted, that were glycoproteins (proteins with carbohydrate groups attached), and proteins that had polymorphisms and sequence variants (gene sequences with some nucleotide differences) were unique to FAP samples.
Proteins found in FAC samples were predicted to interact with other proteins and undertake processes together, including reaction, binding, and activation processes.
“Data from the present study provide evidence that the serum proteomes of patients with ATTRm and healthy age, gender- and race-matched controls are dissimilar,” the researchers wrote. “Our discovery of unique and significant variations in the levels of multiple serum proteins related to ATTRm disease phenotype offers important information, potentially useful as diagnostic indicators and measures of progression in FAC and FAP.
“Moreover, these findings suggest differing pathobiologies in FAC and FAP, and provide data for future mechanistic studies aimed at uncovering new therapeutic targets.”
These proteins can serve as potential biomarkers and provide a basis for future studies to determine the development and mechanisms of these two diseases.