BCS1L mutations produce Fanconi syndrome with developmental disability

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Fanconi syndrome is a proximal tubule disorder with diverse causes, including genetic factors.
• Mitochondrial diseases can manifest with Fanconi syndrome, but often present with systemic symptoms.
• Isolated renal symptoms as the primary presentation of mitochondrial disease are uncommon.

Purpose of the Study:

• To investigate the genetic basis of Fanconi syndrome in two families with developmental disability and mild liver enzyme elevation.
• To identify causative genes and elucidate the pathogenic mechanisms underlying rare mitochondrial diseases presenting with isolated renal symptoms.

Main Methods:

• Whole-exome sequencing (WES) was employed to identify genetic mutations in affected individuals.
• Functional analyses were conducted to establish the pathogenicity of identified mutations in mitochondrial respiratory chain complex III assembly.

Main Results:

• Compound heterozygous known and novel BCS1L mutations were detected in both families.
• These BCS1L mutations were confirmed to impair mitochondrial respiratory chain complex III assembly.
• The identified mutations are associated with Fanconi syndrome and developmental disability.

Conclusions:

• BCS1L mutations leading to mitochondrial respiratory chain complex III deficiency can cause Fanconi syndrome with developmental disability as primary features.
• This study expands the understanding of genotype-phenotype correlations in BCS1L-related mitochondrial disorders.
• Highlights the importance of considering mitochondrial dysfunction in unexplained Fanconi syndrome, even with predominantly renal symptoms.