BCS1L – Mitochondrial Complex III Deficiency

BCS1L encodes an AAA family ATPase essential for the assembly of mitochondrial respiratory chain complex III. Pathogenic variants in BCS1L underlie an autosomal recessive mitochondrial complex III deficiency (MONDO:0015448). Affected individuals present with lactic acidosis, metabolic acidosis, hepatic failure, hypotonia, growth retardation, developmental delay, and encephalopathy. Clinical validity is supported by multiple independent publications over >15 years demonstrating consistent genotype–phenotype correlation.

Genetic evidence includes nine unrelated probands with biallelic BCS1L variants across seven families. A neonatal patient harbored a nonsense p.Arg56Ter allele and two 5′UTR splicing mutations (PMID:19389488). A 4-year-old infant was homozygous for a p.Thr50Ala missense substitution (PMID:19162478). Two Spanish siblings with lactic acidosis carried R45C and p.Arg56Ter alleles segregating with disease (PMID:12910490). Two unrelated children were compound heterozygotes for novel missense and frameshift variants, confirmed by yeast complementation assays (PMID:17403714). Additional single patients with homozygous or compound heterozygous loss-of-function variants have been reported (PMID:20472482; PMID:28427446).

Segregation analysis shows at least two affected relatives in a consanguineous family and segregation in sibling pairs across studies, supporting recessive inheritance. The total number of additional affected relatives with segregating variants is 2.

The variant spectrum encompasses missense (e.g., p.Thr50Ala), nonsense (e.g., p.Arg56Ter), frameshift, splice-site, and UTR-splicing alterations. A representative recurrent allele is c.166C>T (p.Arg56Ter).

Functional assays demonstrate that BCS1L loss-of-function disrupts incorporation of the Rieske iron–sulfur protein into complex III, leading to assembly defects. Yeast complementation of patient alleles and a Bcs1l knock-in mouse model recapitulate biochemical and histopathologic features of human disease, confirming a haploinsufficient mechanism.

Collectively, the genetic and experimental data establish a Strong association between BCS1L and autosomal recessive mitochondrial complex III deficiency, with concordant clinical, biochemical, and animal model evidence. These findings support diagnostic testing in patients with suspected complex III deficiency and inform variant interpretation in clinical practice.

Key Take-home: BCS1L biallelic loss-of-function variants cause autosomal recessive mitochondrial complex III deficiency via impaired assembly of the electron-transport supercomplex, guiding diagnosis and molecular testing.

References

• 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
• Mitochondrion • 2009 • Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency. PMID:19389488
• Neuromuscular disorders : NMD • 2009 • Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. PMID:19162478
• Human molecular genetics • 2007 • Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. PMID:17403714
• Molecular genetics and metabolism • 2010 • Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation. PMID:20472482
• Orphanet journal of rare diseases • 2017 • Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model. PMID:28427446

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