Is the mitochondrial complex I ND5 gene a hot‐spot for MELAS causing mutations?

Abstract

We identified two novel heteroplasmic mitochondrial DNA point mutations in the gene encoding the ND5 subunit of complex I: a 12770A-->G transition identified in a patient with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and a 13045A-->C transversion in a patient with a MELAS/Leber's hereditary optic neuropathy/Leigh's overlap syndrome. Biochemical analysis of muscle homogenates showed normal or very mildly reduced complex I activity. Histochemistry was normal. Our observations add to the evidence that mitochondrial ND5 protein coding gene mutations frequently associate with the MELAS phenotype, and it highlights the role of complex I dysfunction in MELAS.

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

“…Although functional studies of the new sequence variant have to be performed, we consider the T13046C to be the causative mutation in the patient 1 based on its heteroplasmy, strong conservation and absence in several tissues of the unaffected mother of the index patient. Furthermore, A13045C resulting in M237L was recently reported in a patient with MELAS/ LS, 27 who was very similar to our patient 1, which can serve as another evidence supporting the pathogenicity of T13046C.…”

LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation

“…Optic nerve disease in this case has been supported by clinical and electrophysiological data. Comparable findings have been reported in other patients with overlap syndromes harbouring mutations in the MTND5 gene, 6,10 though most mutations causing isolated LHON are found in other (MTND1, MTND4 and MTND6) genes. 19 In conclusion, these data indicate that this mutation is causative and further illustrates both the genetic and phenotypic diversity of mtDNA disorders and the role of complex I dysfunction in both MELAS and LHON.…”

The mitochondrial 13513G>A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff–Parkinson–White

“…We confirm that there is a relationship between severe involvement of the optic nerve and mutations causing amino-acid changes at position D393 in the ND5 protein. 4,10,11 Sudo et al 9 postulated that a WPWS-like cardiac conduction defect is typical of the m.13513G4A mutation since this was described in three of their six patients, whereas two had another cardiac conduction abnormality. Our two cases corroborate this hypothesis.…”

“…Several authors have postulated that the m.13513G4A mutation is a frequent cause of either LS or MELAS and suggested that it should be routinely tested in these patients 3 -6,9,11 even in the absence of a biochemical complex I deficiency. 9,11 The objective of the current study was to determine the frequency of the mutation in a large cohort consisting of 123 patients with an established reduction in complex I enzyme activity. In addition, we review the clinical presentation of the m.13513G4A transition and discuss in which patients it is indicated for a routine molecular diagnostic laboratory, to screen for this mutation.…”

“…The m.13514A4G mutation affects the same codon as the m.13513G4A transition and has been reported in four patients with a MELAS-or LS-like phenotype. 4,10,11 …”