Submission Details

Autosomal recessive

03/22/2019

The NDUFS6 gene is located on chromosome 5 at 5p15.33 and encodes the NADH:ubiquinone oxidoreductase subunit S6 protein. This protein is an accessory subunit of the first enzyme complex in the mitochondrial electron transport chain (complex 1) and aids the transfer of electrons from NADH to the respiratory chain. NDUFS6 was first reported in relation to autosomal recessive mitochondrial complex I deficiency in 2004 (15372108: Kirby et al. 2004). Evidence supporting this gene-disease relationship includes case-level and experimental data. At least five unique variants have been reported in affected individuals in three publications including one recurrent missense variant found in a homozygous state in two individuals of Ashkenazi Jewish origin (thought to be a common founder variant in this population), one splice donor site variant found in a homozygous state in one individual, one intragenic deletion found in a homozygous state in one individual and two frameshift variants found in a compound heterozygous state in one individual (15372108: Kirby et al. 2004; 19259137: Spiegel et al. 2009; 27290639: Pronicka et al. 2016). The mechanism of disease in unknown.This gene-disease relationship is supported by gene-trap knockdown mouse models showing reduced expression of Ndufs6 in cardiac and renal tissues showed the role of complex I in organ function, and the demonstration of reduced complex I activity and defects in mitochondrial function in non-patient cells (22474353: Ke et al. 2012; 23320803: Forbes et al. 2013; 25902503: Kmita et al. 2015). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

15372108 27290639 25902503 22474353 23320803 19259137