Neuropediatrics 2010; 41 - P1311
DOI: 10.1055/s-0030-1265557

Novel Missence Mutation in the BCS1L Gene as a Cause of mitochondrial encephalopathy with Fanconi Syndrome

U Kotzaeridou 1, T Gerstner 1, F Ebinger 1, MF Bauer 2
  • 1Zentrum für Kinder- und Jugendmedizin, Heidelberg
  • 2Institute für Klinische Chemie und Molekulare Diagnostik, Ludwigshafen

Complex III (ubiquinol cytochrome c reductase) of the mitochondrial respiratory chain catalyzes electron transfer from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. Complex III contains 10 nuclear-encoded subunits and 1 mitochondrial-encoded subunit (cytochrome b).

The BCS1L gene is mapped on 2q33 and consists of 7 exons. The bcs1 protein shares sequence similarity with members of the AAA (ATPases associated with various cellular activities) superfamily and facilitate insertion of Rieske Fe/S protein into precursors to complex III. Complex III then becomes assembled with complexes IV and I into a respirasome supercomplex that facilitates the electron transfer required for the synthesis of ATP.

Mutations in the BCS1L gene lead to isolated complex III deficiency and are associated with tubulopathy, encephalopathy, and liver failure. BCS1L gene mutations are also a major cause of GRACILE (growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death) and Björnstad syndrome (sensorineural hearing loss and pili torti).

BCS2L mutations cause widely different clinical phenotypes. Studies showed that all BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit of respiration in human mitochondria), but the clinical severity of the mutations was correlated with the production of reactive oxygen species. The data indicated that in addition to mitochondrial heteroplasmy and variable energy requirements of tissues, tissue-specific sensitivities to reactive oxygen species contribute to the variability of the manifestations of mitochondrial defects.

Here we describe a 9-year-old male patient with hyperlactacidemia, mild liver dysfunction, hypotonia, Fanconi syndrome, growth, and psychomotor retardation and mitochondrial complex III deficiency in muscle tissue. Genetic analysis of the BCS1L gene revealed a novel homozygous point mutation, c.142A>G causing a pM48V substitution with the highly conserved internal import signal of the chaperone.

Both parents were heterozygous for the deleterious transitions. The unaffected sisters were heterozygous for the wild type allele. Although, the amino acid substitution is predicted to be benign, yeast complementation analyses provide strong evidence that pM48V is the causative mutation responsible for the singular clinical phenotype in our patient.