Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A>G Variant

• DOI: 10.3390/ijms26083670
• Publication Date: 2025-04-14T10:18:36Z
• Authors: Valeria Capaci; Luisa Zupin; Martina Magistrati; Maria Teresa Bonati; Fulvio Celsi; Irene Marrone; Francesco Baldo; Blendi Ura; Beatrice Spedicati; Anna Morgan; Irene Bruno; Massimo Zeviani; Cristina Dallabona; Giorgia Girotto; Andrea Magnolato

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe2S2 iron–sulfur Rieske protein into nascent electron transfer complex III. Variants in are associated with spectrum of disorders, ranging from mild to severe phenotypes. Björnstad syndrome, milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More disorders include Complex III Deficiency, leads neuromuscular metabolic dysfunctions multi-systemic issues Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, Lactic Acidosis syndrome (GRACILE). severity these conditions varies depending on specific mutation its impact function. This study describes 27-month-old child SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, alterations. Genetic analysis revealed homozygous variant (c.38A>G, p.Asn13Ser), previously reported patient more phenotype that, however, was not functionally characterized. In this work, functional studies yeast model patient-derived fibroblasts demonstrated that impairs respiration, activity (CIII), also alters morphology affected fibroblasts. Interestingly, we unveil new possible mechanism pathogenicity for mutant protein. Since interaction between CIII increased, suggests formation BCS1L-containing nonfunctional preCIII unable load RISP complete assembly. These findings support c.38A>G variant, suggesting altered CIII.