Transition m.3308T>C in the ND1 Gene Is Associated with Left Ventricular Hypertrabeculation/Noncompaction

Abstract

Though left ventricular hypertrabeculation/noncompaction (LVNC) is frequently associated with mitochondrial DNA (mtDNA) mutations, it has not been reported in association with the transition m.3308T>C of the NADH dehydrogenase subunit 1 (ND1) gene. The index patient is a 16-year-old Tunisian female who was investigated for a systolic murmur and cardiomegaly. Echocardiography revealed tricuspid insufficiency, moderate left ventricular dilatation, Ebstein’s anomaly, a superior caval vein draining into the coronary sinus and, surprisingly, LVNC of the apex and the lateral wall. LVNC was absent in all other cardiologically investigated siblings. RNA and mtDNA sequence analysis revealed the known homoplasmic mutation m.3308T>C resulting in the replacement of the first amino acid methionine by threonine in the ND1 subunit of respiratory chain complex I. The m.3308T>C mutation was also present in the patient’s mother and several other family members but absent in 350 controls. Additionally, the index patient carried the polymorphisms m.8248A>G in the COX2 gene and m.8468C>T in the ATP8 gene. It is concluded that LVNC may be associated with the known homoplasmic m.3308T>C mutation in the ND1 gene. However, the pathogenetic role of this mutation in the development of LVNC remains elusive.

Raising Doubts about the Pathogenicity of Mitochondrial DNA Mutation m.3308T>C in Left Ventricular Hypertraveculation/Noncompaction

“…Recently, Zarrouk Mahjoub et al [1] claimed that the homoplasmic mutation m.3308T>C located in the NADH dehydrogenase subunit 1 (ND1) gene of the mitochondrial DNA (mtDNA) genome was associated with left ventricular hypertrabeculation/noncompaction (LVNC). The authors observed this mutation in a 16-year-old Tunisian female patient and other matrilineal related members, but it was absent in their 350 controls.…”

“…In addition to the transition m.3308T>C, the authors reported two additional changes, m.8248A>G (COX2 gene) and m.8468C>T (ATP8 gene). Although it is essential to show all variants observed in the mtDNA of the patients, (so that a detailed haplogroup assessment can be made), no other information was reported by Zarrouk Mahjoub et al [1] regarding the mtDNA genome of this matrilineage.…”

“…However, the literature was not extensively discussed by Zarrouk Mahjoub et al [1], with studies critical to the interpretation of the seeming pathogenicity of m.3308T>C being overlooked. Rocha et al [2] was the only study from the body of relevant literature cited by Zarrouk Mahjoub et al [1], but only with reference to the fact that ‘...[m.3308T>C] has been reported in various other human populations, especially in the West African haplogroup...’ [2]. The study by Zarrouk Mahjoub et al [1] did not, however, refer to the fact that Rocha et al [2] suggested that m.3308T>C was a benign variant.…”

“…Rocha et al [2] was the only study from the body of relevant literature cited by Zarrouk Mahjoub et al [1], but only with reference to the fact that ‘...[m.3308T>C] has been reported in various other human populations, especially in the West African haplogroup...’ [2]. The study by Zarrouk Mahjoub et al [1] did not, however, refer to the fact that Rocha et al [2] suggested that m.3308T>C was a benign variant. Here we elaborate further on evidence favoring a benign role for m.3308T>C in LVNC, but the rationale can be extended to other putative pathogenic variants.…”

“…The first line of evidence put forth by Zarrouk Mahjoub et al [1] was that evolutionary comparisons indicated that the m.3308 residue was highly conserved throughout evolution. However, m.3308T>C is not a rare variant but rather a common polymorphism found in various geographic locations, including Tunisia.…”