BCS1L – GRACILE syndrome

GRACILE syndrome (MONDO:0011308) is a severe autosomal recessive mitochondrial hepatopathy characterized by fetal growth restriction, Fanconi-type aminoaciduria, cholestasis, lactic acidosis, iron overload, coagulopathy, hypoglycemia and early death. It is caused by biallelic pathogenic variants in BCS1L, which encodes a mitochondrial AAA ATPase essential for incorporation of the Rieske iron–sulfur protein into complex III of the respiratory chain.

Initial case reports described a 2-month-old boy homozygous for c.296C>T (p.Pro99Leu) (PMID:24655110) presenting with fetal growth restriction, lactic acidosis, cholestasis, coagulopathy and early death. A Finnish cohort of 25 infants from 18 families homozygous for c.232A>G (p.Ser78Gly) supported a founder effect in the Finnish disease heritage (PMID:12547234). Three British infants harbored distinct missense and truncating alleles (PMID:12215968), and a Turkish kindred exhibited four patients with homozygous p.Pro99Leu variants (PMID:29090881). Novel compound heterozygous alleles c.231_232del (p.Ser78CysfsTer9) and c.245C>T (p.Ser82Leu) further expanded the mutational spectrum (PMID:35960161).

Affected sibships include two similarly affected sisters in the Turkish family demonstrating segregation of pathogenic alleles in trans (PMID:29090881). Additional consanguineous and outbred pedigrees confirm autosomal recessive inheritance and segregation of BCS1L variants with disease.

Pathogenic variants include over 30 distinct alleles comprising more than 15 truncating mutations (nonsense, frameshift, splice) and over 10 missense changes. The c.232A>G (p.Ser78Gly) founder allele predominates in Finnish patients (PMID:12215968). Other recurrent alleles include c.296C>T (p.Pro99Leu) in Turkish patients and unique private variants such as c.231_232del (p.Ser78CysfsTer9).

Functional studies demonstrate that missense and truncating BCS1L variants impair Rieske protein incorporation and complex III assembly, leading to decreased complex III activity and elevated reactive oxygen species in patient fibroblasts and yeast complementation models (PMID:17403714; PMID:20518024). A Bcs1l knock-in mouse carrying the GRACILE mutation recapitulates growth failure, hepatic steatosis, fibrosis, renal tubulopathy and residual complex III activities of ~20% in symptomatic tissues (PMID:21274865).

The large number of unrelated cases, multisib segregation, and concordant functional data fulfill ClinGen criteria for a Definitive gene–disease association. Molecular testing of BCS1L enables precise diagnosis, carrier screening and prenatal diagnosis in at-risk families. Key take-home: BCS1L loss-of-function variants cause GRACILE syndrome by disrupting complex III assembly, supporting inclusion in mitochondrial diagnostic panels.

References

• Blood cells, molecules & diseases • 2002 • The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. PMID:12547234
• American journal of human genetics • 2002 • GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. PMID:12215968
• Renal failure • 2014 • BCS1L gene mutation causing GRACILE syndrome: case report. PMID:24655110
• The Turkish journal of pediatrics • 2016 • A Turkish BCS1L mutation causes GRACILE-like disorder. PMID:29090881
• Nephrology (Carlton, Vic.) • 2022 • Identification of two novel variants of BCS1L gene in a patient with classical GRACILE syndrome. PMID:35960161
• Hepatology (Baltimore, Md.) • 2011 • The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy. PMID:21274865
• Human mutation • 2010 • Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency. PMID:20518024
• Human molecular genetics • 2007 • Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. PMID:17403714

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