BCS1L-Associated Disease: 5'-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy.

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Neurogenetics

Background:

• BCS1L gene mutations are associated with mitochondrial disorders.
• Understanding genotype-phenotype correlations is crucial for diagnosing and managing these complex conditions.
• The role of regulatory variants in disease severity is an emerging area of research.

Purpose of the Study:

• To investigate the pathogenic impact of a BCS1L missense variant (c.838C>T; p.L280F) and a 5 étaire-UTR variant (c.-122G>T).
• To elucidate how these variants influence disease pathogenesis, clinical presentation, and severity in affected siblings.
• To expand the understanding of BCS1L-related disorders and the role of regulatory elements in disease modulation.

Main Methods:

• Deep phenotyping and whole genome sequencing were employed to identify genetic variants.
• Biochemical characterization of identified BCS1L variants was performed.
• Studies in patient-derived fibroblast cultures assessed variant pathogenicity and response to therapeutic agents.

Main Results:

• A pathogenic missense variant (p.L280F) and a 5 étaire-UTR variant (c.-122G>T) in BCS1L were identified in affected siblings.
• The missense variant disrupts mitochondrial complex III assembly, while the 5 étaire-UTR variant allows for residual wild-type BCS1L expression, mitigating disease severity.
• Biochemical analyses confirmed variant pathogenicity and showed a moderate in vitro response to a coenzyme Q10 analog.

Conclusions:

• This study identifies a milder phenotype of BCS1L-related disorder involving central and peripheral nervous system dysfunction.
• The 5 étaire-UTR variant modulates disease severity by enabling residual gene expression, partially counteracting the effects of the missense variant.
• Evaluating both coding and regulatory variants is essential for accurate diagnosis and understanding the pathogenesis of mitochondrial diseases.