A Turkish BCS1L mutation causes GRACILE-like disorder.

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Mitochondrial disorders can present with severe neonatal complications.
• The Finnish GRACILE syndrome, caused by BCS1L mutations, affects infants with growth restriction, lactic acidosis, and organ failure.
• Genetic variations in BCS1L are implicated in mitochondrial complex III assembly defects.

Purpose of the Study:

• To investigate the genetic basis of a severe neonatal condition resembling GRACILE syndrome.
• To identify mutations in the BCS1L gene in a patient with lactic acidosis, renal tubulopathy, and cholestasis.
• To characterize the functional consequences of a novel BCS1L mutation.

Main Methods:

• Genetic sequencing of the BCS1L gene.
• Analysis of patient's clinical presentation and family history.
• Comparison with previously reported cases of BCS1L-related disorders.

Main Results:

• A homozygous c.296C > T (p.P99L) mutation was identified in the BCS1L gene of the patient.
• The patient presented with severe lactic acidosis, renal tubulopathy, cholestasis, and elevated ferritin, consistent with a mitochondrial disorder.
• The same mutation was found in affected siblings and is associated with complex III deficiency, encephalopathy, and liver failure in Turkish populations.

Conclusions:

• The p.P99L mutation in BCS1L is a likely cause of a GRACILE-like syndrome, predominantly observed in the Turkish population.
• This mutation leads to mitochondrial respiratory chain complex III deficiency and severe multi-organ dysfunction.
• Investigating assembly defects in complex III within affected tissues is crucial, as fibroblast analysis may not reveal the deficiency.