A novel compound heterozygous mutation in NFU1 as cause of iron-sulfur cluster biosynthesis

Background: Recently, mutations have been detected in NFU1 and BOLA3, two genes involved in iron-sulfur biogenesis. In affected patients, defects in the OXPHOS complexes I and II, in 2-oxoacid dehydrogenase and in lipoate synthesis were found. The objective was to screen our database of patients to find patients with similar clinical and biochemical findings and to sequence the two genes in suspected patients. Methods: Patients with encephalopathy, failure to thrive, hyperlactacidemia, increased glycine in cerebrospinal fluid and decreased activities of the complexes I and II were selected. BN-PAGE, western blotting and Sanger sequencing was performed. Results: A decreased protein amount in the complexes I and II was visualized using BN-PAGE. A decrease of structural subunits in complexes I and II and low signals of protein-bound lipoic acid were detected by western blotting. Mutations were detected in NFU1 in both patients. One patient carried the 'hotspot' mutation p.Gly208Cys and the other was a compound heterozygote for this mutation and for p.Arg21Pro. Conclusion: Only three papers were reported earlier in the literature describing patients with NFU1 deficiency. Our results are concordant with the assumed role of NFU1 in ISC biosynthesis and a novel compound heterozygous mutation is presented here.