Mitochondrial DNA mutations as a potential modifier for the clinical variability of Marfan syndrome

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Medicine
• Cardiovascular and Ocular Genetics

Background:

• Marfan syndrome (MFS) is an autosomal genetic disorder caused by FBN1 mutations, characterized by variable patient phenotypes despite identical FBN1 mutations.
• Mitochondrial dysfunction is implicated in MFS, observed in patient aortas and animal models, but the role of mitochondrial DNA (mtDNA) mutations remains unclear.
• Single nucleotide variants in mtDNA can negatively impact cellular function, warranting investigation into their association with MFS.

Purpose of the Study:

• To investigate the association between mitochondrial DNA (mtDNA) mutations and Marfan syndrome (MFS).
• To determine if mtDNA mutations act as modifiers of MFS phenotypes, influencing disease severity and specific manifestations.
• To analyze the frequency and mutation rate of mtDNA variants in MFS patients compared to healthy controls.

Main Methods:

• Targeted mtDNA sequencing was performed on whole blood samples from 77 MFS patients and 48 healthy controls.
• Analysis included 7 mother-offspring pedigrees to trace inheritance patterns of mtDNA mutations.
• Identified mtDNA mutations were correlated with clinical phenotypes, including eye lesions and aortic manifestations.

Main Results:

• Three rare mtDNA mutations (m.279T > C, m.2361G > A, m.3316G > A) were found in a family with predominant eye lesions; patients with these mutations showed more severe symptoms.
• The mtDNA mutation m.9738G > A was identified in a family with aortic disease, and a sporadic MFS case with this mutation had an aortic aneurysm.
• MFS patients exhibited a higher frequency of all variants, nonsynonymous variants, pathogenic/likely pathogenic variants, and variants of uncertain significance compared to controls.
• The mutation rate in the coding region, MT-rRNA, and MT-tRNA was elevated in the MFS group.

Conclusions:

• Mitochondrial DNA mutations are frequently observed in Marfan syndrome patients.
• Specific mtDNA mutations may act as potential modifiers of MFS phenotypes, influencing the severity and type of clinical manifestations.
• Further research is warranted to elucidate the precise mechanisms by which mtDNA mutations contribute to MFS pathogenesis.