Biomedical subjects

Marisa W Friederich

Publications and source records attributed to Marisa W Friederich.

3 recordsLinked to original sources

PubMed2026

Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease.

Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.

Journal Article↗

PubMed2026

Unusual Variants in NDUFAF6-Associated Mitochondrial Disease.

A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6, i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.

Mitochondrial disease↗

PubMed2025

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.

Humans↗