Submission Details

Autosomal recessive

02/24/2020

The TIMMDC1 gene is located on chromosome 3 at 3q13.33 and encodes the translocase of inner mitochondrial membrane domain containing 1 protein. This protein functions as a membrane-embedded assembly factor for complex I of the mitochondrial respiratory chain. TIMMDC1 was first reported in relation to autosomal recessive mitochondrial complex I deficiency, nuclear type in 2017 (28604674: Kremer et al. 2017). To date, a single deep intronic variant that disrupts splicing has been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. The deep intronic variant was reported in a homozygous state in three unrelated individuals of differing ethnicities in a single publication (28604674: Kremer et al. 2017). The variant also segregated with the disease in two additional family members. Loss of function is the mechanism of disease. This gene-disease relationship is also supported by expression data, a role in complex I assembly/function shared with other genes associated with mitochondrial disease, rescue of impaired complex I assembly in patient cells by the expression of WT TIMMDC1, and in vitro evidence that TIMMDC1 depletion in human cells impairs mitochondrial function, including a specific loss of complex I activity, reduced oxygen consumption, disrupted mitochondrial morphology, and reduced complex I assembly (24344204: Guarani et al. 2014; 25613900: Uhlén et al. 2015; 28604674: Kremer et al. 2017). 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.

28604674 24344204 25613900