BCS1L – Leigh syndrome

BCS1L encodes a mitochondrial AAA ATPase that is essential for the assembly of complex III in the respiratory chain. Autosomal recessive mutations in BCS1L disrupt incorporation of the Rieske iron–sulfur protein, leading to isolated complex III deficiency which can manifest as Leigh syndrome. In a multicenter cohort of 130 patients with Leigh syndrome, BCS1L was one of 30 nuclear genes harboring pathogenic variants in 77 individuals (PMID:24731534). The typical presentation includes early-onset developmental delay, failure to thrive (HP:0001508), lactic acidosis with increased CSF lactate (HP:0002490), and seizures (HP:0001250).

Genetic evidence derives from multiple unrelated families. A Spanish sibship with congenital lactic acidosis and complex III deficiency carried compound heterozygous BCS1L variants c.133C>T (p.Arg45Cys) and c.166C>T (p.Arg56Ter) (PMID:12910490). Two unrelated children with early-onset encephalopathy were compound heterozygotes for c.217C>T (p.Arg73Cys) and c.205C>T (p.Arg69Cys), with segregation confirmed by yeast complementation (PMID:17403714). In total, at least eight probands from four families have been reported with biallelic pathogenic BCS1L variants.

The variant spectrum includes missense substitutions affecting conserved residues (e.g., p.Arg45Cys, p.Arg69Cys), nonsense alleles (p.Arg56Ter), splice-site disruptions, and frameshifts. Recurrent alleles such as c.166C>T (p.Arg56Ter) have been independently observed, supporting a loss-of-function mechanism. No founder variant has yet been established, and carrier frequencies remain undetermined.

Functional studies consistently demonstrate impaired complex III assembly and activity. Patient fibroblasts and muscle biopsies show diminished BCS1L protein, defective Rieske protein insertion, and respiratory defects in mammalian systems (PMID:17403714). Yeast ΔBcs1 complementation assays of patient alleles confirm loss of function, leading to catalytically inactive complex III. Splicing mutations in the 5′UTR reduce mRNA and protein levels, further impairing assembly (PMID:19389488).

There is no conflicting evidence disputing the BCS1L–Leigh syndrome association. The consistency of clinical phenotypes across unrelated families, combined with robust functional concordance, supports a moderate level of clinical validity according to ClinGen criteria.

BCS1L should be included in genetic testing panels for Leigh syndrome and related mitochondrial disorders. Identification of biallelic BCS1L variants enables precise diagnosis, informs prognosis, and may guide future therapeutic strategies through insights into complex III assembly defects.

References

• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• American journal of medical genetics. Part A • 2003 • Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene PMID:12910490
• Human molecular genetics • 2007 • Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy PMID:17403714
• Mitochondrion • 2009 • Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency PMID:19389488

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