A novel mitochondrial DNA m.7507A>G mutation is only pathogenic at high levels of heteroplasmy

• Novel disease-causing mutation in the mitochondrial tRNASer(UCN) gene.
• Clinical spectrum: fatal lactic acidosis, hearing loss and exercise intolerance.
• Homoplastic levels of this mutation affect assembly of complexes I and IV.
• Homoplastic levels of this mutation reduce steady-state level of mt-tRNASer(UCN).

We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNASer(UCN) gene, m.7507A>G. The index patient died during the neonatal period due to cardio–respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNASer(UCN) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 ± 4% in blood and 68 ± 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy.