Table 2 of
Bosley, Mol Vis 2007;
13:1516-1528.Table 2 of
Bosley, Mol Vis 2007;
13:1516-1528.
Table 2. Non-synonymous mitochondrial DNA sequence changes detected in optic neuritis patients
This table assesses each nucleotide change in patients not previously found to be haplogroup-specific polymorphism as described in Methods. "Transversion" is a mutation in which a purine/pyrimidine replaces a pyrimidine/purine base pair or vice versa (G:C>T:A or C:G, or A:T>T:A or C:G), and "Transition" is a mutation in which a purine/pyrimidine base pair is replaced with a base pair in the same purine/pyrimidine relationship (A:T>G:C or C:G>T:A). "Controls (%)" represents percent of controls with this nucleotide substitution. "Heteroplasmy (%)" represents percent of mutant DNA present. "NA" represents not applicable because the nucleotide change was always found in homoplasmic state. To determine novelty, previous reports of sequence variants were found in the MITOMAP database, the human mitochondrial Genome database, GenBank, and Medline listed publications. Interspecies conservation was assessed using PolyPhen, which determines interspecies conservation for an altered amino acid by performing alignment with all available amino acid sequences for other species, and the Mamit-tRNA website when necessary. PolyPhen predicts and displays secondary structural characteristics. "Yes" indicates nucleotide change will alter protein secondary structure; "No" indicates change will not alter secondary structure. PolyPhen prediction of pathogenicity was assessed utilizing the PolyPhen database. "Probably damaging" constitutes a high confidence of affecting protein function or structure. "Possibly damaging" reflects a likelihood of affecting protein function or structure, while "Benign" changes most likely lack phenotypic effect. "Unknown" means that PolyPhen could not make a prediction due to lack of data. The Sorting Intolerant from Tolerant website (SIFT) returns predictions for which amino acid substitutions will affect protein function. "Yes" means an amino acid change is predicted to affect protein function, while "No" means the amino acid change is not predicted to affect protein function. Summary: A sequence variant was considered potentially pathologic if it satisfied all the following conditions, where possible: it changed a moderately or highly conserved amino acid; Protean predicted an alteration of protein structure; it was predicted by SIFT to have an effect on protein function; and it was assessed as possibly or probably pathogenic by PolyPhen.
Base
Nucleotide AA substitution Controls Hetero-plasmy Interspecies
substitution change Location type (%) (%) Novel conservation Protean PolyPhen SIFT Summary
------------ ------ ------------------------ ------------ -------- ------------- ----- ------------ ------- -------- ---- --------------
3580 C>A P92T Functional domain of ND1 Transversion 0 70 Yes High Yes Probably Yes Pathologic
gene damaging
4136 A>G Y277C Outside the TM domain of Transition 0 NA No High Yes Possibly Yes Pathologic
ND1 gene damaging
4370 T>C N/A Anticodon loop of tRNA Transition 0 65 No Moderate NA NA NA Pathologic
glutamine
5089 T>G I207S TM domain of ND2 gene Transversion 0 NA Yes High Yes Probably Yes Pathologic
damaging
5516 A>C N/A Acceptor stem in tRNA Transversion 0 63 No High NA NA NA Pathologic
tryptophan
6261 G>A A120T TM domain of COI gene Transition 0 NA No Moderate Yes Possibly Yes Pathologic
damaging
6880 C>A T326K TM domain of COI gene Transversion 0 65 Yes High Yes Probably Yes Pathologic
damaging
8813 C>A T96N Outside the TM domain of Transversion 0 50 Yes High Yes Probably Yes Pathologic
ATPase 6 gene damaging
9104 T>C F193S Outside the TM domain of Transition 0 NA Yes High No Benign No Non-pathologic
ATPase 6 gene
9300 G>A A32T TM domain of COIII gene Transition 1.2 NA No Moderate No Benign No Non-Pathologic
9904 T>G F233C Outside the TM domain of Transversion 0 NA Yes High Yes Probably Yes Pathologic
COIII gene damaging
9948 G>A V248I TM domain of COIII gene Transition 0 NA No High Yes Probably Yes Pathologic
damaging
10946 A>G T63A TM domain of ND4 gene Transition 0 NA Yes Moderate No Benign No Non-pathologic
11865 T>G L369W In the TM functional Transversion 0 NA Yes Moderate Yes Probably Yes Pathologic
domain of ND4 damaging
13253 C>G T306S In the TM functional Transversion 0 NA Yes High Yes Probably Yes Pathologic
domain of ND5 damaging
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