Twelve Japanese patients with POLG-related disorders: Population-specific genetic differences of POLG variants in...

POLG encodes mitochondrial DNA (mtDNA) polymerase γ. Pathogenic POLG variants cause mitochondrial diseases, including progressive external ophthalmoplegia. POLG-related disorders are relatively common in Europe, possibly because of the high prevalence of carriers in the general population, but remain rare in Japan for unclear reasons.

We performed long-range PCR on mtDNA from skeletal muscle and/or peripheral blood from 3146 patients with suspected mitochondrial disease between 1993 and 2021. We selected 167 individuals with clinical features suggestive of POLG-related disorders for POLG gene analysis; all lacked pathogenic mtDNA point mutations, and most had multiple mtDNA deletions and/or a family history of mitochondrial disease.

Among the 167 patients (median age: 52 years, range: 0-83 years, 11% pediatric cases), we identified 12 Japanese patients with POLG-related disorders and six POLG variants, including one novel variant. The six variants were p.Y955C, p.R943H, p.T599I, p.M299L, p.Y1210* (c.3626_3629dupGATA), and the novel variant p.F377S (c.1130T>C). Neither these six variants nor the 10 previously reported cases from Japan included the POLG variants that are more frequent in Europe. We also analyzed three population databases: two whole-genome sequencing databases covering 61,000 and 9850 Japanese individuals, respectively, and one global population database (gnomAD) covering 730,000 individuals worldwide. POLG variants that are more frequent in Europe were not detected in the Japanese databases or among East Asian individuals in gnomAD.

Our findings suggest population-specific genetic differences in POLG between Japanese and European populations, explaining the lower frequency of POLG-related disorders in Japan.