Bi-allelic NDUFA6 Variants Are Identified in Four Unrelated Subjects
(A) Family pedigrees of subjects 1–4 and corresponding sequencing chromatograms presenting compound-heterozygous c.191G>C (p.Arg64Pro) and c.265G>T (p.Glu89∗) NDUFA6 variants in subject 1, the homozygous NDUFA6 deletion c.331_332del (p.Glu111Serfs∗35) in subject 2, the homozygous c.3G>A (p.?) NDUFA6 variant in subject 3, and compound-heterozygous c.309del (p.Met104Cysfs∗35) and c.355del (p.Leu119Tyrfs∗20) NDUFA6 frameshift mutations in subject 4. Abbreviations are as follows: S, subject; C, wild-type control.
(B) Analysis of the resolved crystal structure of complex I revealed spatial proximity of the Arg64 NDUFA6 residue with two negatively charged and highly conserved NDUFAB1 residues, Lys92 and Asp114. These most likely represent critical binding interactions between the two proteins during late complex I assembly.
(C) Alignment of the three in-frame NDUFA6 transcripts demonstrates that ENST00000602404 (GenBank: NM_002490.5) uses an initiator methionine downstream of that used by ENST00000498737 (GenBank: NM_002490.4). The shortest transcript, ENST00000470753, initiates downstream of the highly conserved LYR motif (shaded yellow) that is reported to be critical for binding the mitochondrial acyl carrier (encoded by NDUFAB1); the function of this isoform therefore remains unknown. Subject variants are shaded blue.