LETTER TO THE EDITOR An evolutionary insight into mutation of ATPase6 gene in primary ovarian insufficiency S. Venkatesh • Rima Dada Received: 30 August 2010 / Accepted: 30 November 2010 / Published online: 17 December 2010 Ó Springer-Verlag 2010 In our earlier study [1], we reported the association of primary ovarian insufficiency (POI) with non-synonymous mutations in the ATPase6 gene. It has been claimed that these changes are phylogenetic dependent and are not associated with the POI [2]. It has also been quoted that out of the six mutations reported in the ATPase6 gene, five were attributable to distinct south Asian, West Eurasian and East Asian haplogroups’. However, it is not acceptable at this point of view as five different ethnicities or haplo- groups cannot be classified based on only these five dif- ferent mitochondrial substitutions. After the published comment on our findings, we did an intensive study of mtDNA haplogroups of each patient samples and found that on the basis of single mitochondrial substitution, the whole lineage cannot be defined and so their haplogroups. Every individual whether it is a case or control, falls under a specific haplogroup which is char- acterized by the series of homoplamsic mitochondrial mutations. If any non-synonymous mutation is found in mitochondrial genome which is not a part of individual specific phylogenetic lineage then it may alter the health profile of the same individual and hence included in our study as pathogenic [1]. Moreover, if the transitions occur in the coding region and interestingly if they are non- synonymous mutations changing the chemical nature of the amino acid, the individual carrying this may be more susceptible for the disease. Thus, the severity of mutations to the health of any individual is not affected by whether they are phylogenetic dependent or not. Moreover, our study is strictly based on clinical association, where cases had high ROS levels, and was not intended for phyloge- netic analysis. After an intensive study of mtDNA haplogroups (Table 1), importantly, the virtual absence of transitions at 8137 and 8584 suggests that the patients are neither falling in M8 nor in U7 haplogroup. Instead, the presence of 8502 transition in the sample containing 8684C mutation sug- gests that they fall in M2 haplogroup [3]. This mutation is present in 7 out of 20 patients. In addition to that the absence of 1811T mutation in the cases suggests yet another evidence contrary to comments, as the presence of 1811T is mandatory to define either M39 or U2 0 3 0 4 0 7 0 8 0 9 haplogroup [4, 5]. Moreover, the frequently found 12705T with 9094C (which is present in 5 out of 20 patients) was claimed to be overwhelming Indian specific R haplogroup instead of U2b2, whereas the non-synonymous 9094C has never been reported as a part of macro haplogroup R. Hence, now the correlation is more positive between 8684C, 9094G and occurrence of POI. We have also not found any nine base pair deletion (represents B4 and B5 haplogroup) in the samples having 9123G transition which was claimed to fall in B4a haplogroup. At last, the non- synonymous mutation 9064G was claimed to be present in four different haplogroups and intriguingly they all belong to macro haplogroup M, but surprisingly we have found 10398G instead of 10400T which shows that this sample may fall in any haplogroup but not in M. In addition to this, we have also initiated another study enrolling more cases on these aspects to come to a conclusion, because reactive oxygen species are by product of mitochondrial respiratory chain and may be produced in excess in cases with mito- chondrial dysfunction due to mitochondrial nucleotide changes [6]. We further strongly state that the results of our preliminary pilot study [1] highlights the need for larger S. Venkatesh Á R. Dada (&) Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India e-mail: rima_dada@rediffmail.com 123 Arch Gynecol Obstet (2011) 284:251–252 DOI 10.1007/s00404-010-1807-4