Novel mutations of the OPA1 gene in Chinese dominant optic atrophy.
OBJECTIVE
To investigate OPA1 gene mutations in Chinese patients with autosomal dominant optic atrophy and sporadic optic atrophy.


METHODS
Molecular genetic studies and observational case series.


METHODS
Twenty-four patients from 10 unrelated Chinese pedigrees of autosomal-dominant optic atrophy, 35 isolated cases with bilateral optic atrophy of unknown cause, and 50 unrelated normal controls.


METHODS
Genomic DNA was extracted from peripheral blood leukocytes. All 28 coding exons of the OPA1 gene and flanking intron splice sites were sequenced. Putative mutations were reexamined for segregation in the respective families by direct sequencing. Further characterization of selected splicing site mutations was performed by reverse transcription-polymerase chain reaction (PCR) of each patient's leukocyte mRNA.


METHODS
Direct sequencing of the OPA1 gene.


RESULTS
Four OPA1 gene mutations were detected, including 2 splicing site mutations (c.1065+2T>C on intron 10 and c.1212+2insT on intron 12), 1 deletion (c.1776_1778delACT on exon 19), and 1 missense mutation (c.2846 T>C on exon 28). The c.1212+2insT, c.1776_1778delACT, and c.2846T>C mutations were newly identified OPA1 mutations. Reverse transcription (RT)-PCR and direct sequencing revealed that the splicing site mutations on c.1065+2T>C and c.1212+2insT caused skipping of exons 10 and 12, respectively. The c.1776_1778delACT mutation led to a deletion of the Leu amino acid on residue 593. OPA1 mutations were found in 4 of 10 familial cases (40 %) and in 1 of 35 sporadic cases of optic atrophy.


CONCLUSIONS
OPA1 gene mutations are causative in Chinese autosomal-dominant optic atrophy and sporadic optic atrophy. Screening for OPA1 gene mutations in patients with childhood onset optic atrophy who have no affected relatives is useful in making the diagnosis.
Yen
May-Yung
MY
Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan. myyen@vghtpe.gov.tw
Wang
An-Guor
AG
Lin
Yen-Ching
YC
Fann
Ming-Ji
MJ
Hsiao
Kwang-Jen
KJ
D000328:Adult; D044466:Asian People / Q000235:genetics*; D002648:Child; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D017931:DNA Primers; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human