Browsing by Author "Hinterding, Helena"

Early-onset cardiomyopathies (CMPs) are disorders that bring a heavy burden for families as they often lead to early death among children. CMP may be defined as a disease affecting the myocardium and its ability to pump blood efficiently. While CMPs can be both of acquired and hereditary origin, heterogeneous genetics often explain the early onset of such diseases with varying phenotypes. This study aimed to offer molecular diagnoses to three patients within the ‘KidCMP cohort’ (n=74, University Hospital Helsinki) and characterize their disease-causing genes in early-onset CMPs. Additionally; it aimed to develop patient-specific tools to study disease mechanisms in more detail. While candidate pathogenic variants were identified through whole-exome sequencing, the validation of these variants was approached through experimental work at RNA and protein level as well as molecular modeling. Using whole-exome sequencing data, we identified novel candidate disease genes in three patients from the ‘KidCMP’ cohort: TMOD1, NRAP and PGM5. While NRAP has been previously reported in a family with autosomal dominant transmission of adult dilated CMP and incomplete penetrance, TMOD1 and PGM5 have not been previously associated with disease. TMOD1 (Tropomodulin-1) presented a homozygous missense mutation in our patient, and the conservation in species and molecular modeling of the identified variant further supported its underlying role in teenage-onset dilated CMP. Cytoskeletal stability and sarcomeric force transmission are likely to be disrupted as a result of the mutation in this actin-binding protein. NRAP (Nebulin-related-anchoring protein) presented a homozygous nonsense mutation in the second patient and RNA analysis from cells and heart tissue revealed mRNA to escape nonsense-mediated decay. This gene occupies an important role in myofibril assembly and anchoring actin filaments to the cell membrane. Based on the induced premature stop codon we judged this variant to lead to a loss of function and to underlie severe early-onset dilated CMP in our patient. PGM5 (Phosphoglucomutase-like protein 5) presented a compound heterozygous missense mutation in the third patient and protein analysis revealed the affected protein to be present in reduced form. PGM5 interacts with actin filaments and occupies an important role in myofibril formation as well as cell-cell contact. Homology modeling showed the variants to cluster in the disease-associated region of the homologous PGM1 gene. Based on this, we judge this variant to underlie early-onset dilated CMP in our patient. Overall, these findings suggest a valuable role of whole-exome sequencing in disclosing the heterogeneous genetic background of this field of diseases. By identifying and characterizing novel disease genes as presented here, we offer important knowledge for targeted treatment options and further research.