The unresolved origin of uniparental diploid cell lines

29 10 2009

To the Editor:

I should like to comment on the interesting report of Morales et al. (1) describing prenatally detected cases of androgenetic/biparental mosaicism.

Two mechanisms of origin have been discussed for case 1 that represent a mixture of androgenetic 46,XX and normal biparental 46,XY cells. One alternative involves dispermic fertilization of an oocyte and formation of a triploid zygote followed by a ‘division without replication’ and missegregation of the paternal pronuclei. In the resulting 2n/n mosaic, endoreduplication of the haploid paternal genome would finally create the diploid androgenetic cell line.

This example resembles our observation of an oocyte with three pronuclei that underwent a premature irregular cytokinesis including one of the pronuclei in the smaller half of the divided cytoplasm (2). We surmised that isolation of the supernumerary pronucleus by premature cytokinesis might be relevant for diploidization of triploid zygotes and also for the development of haploid/diploid mosaics or diploid uniparental cell lines. Though the oocyte described by us obviously had two maternal pronuclei, the corresponding mechanism is also applicable to a dispermic oocyte. Here, one half of the divided ooplasm could receive the maternal pronucleus and one of the paternal pronuclei, giving rise to a diploid biparental cell line. The second paternal pronucleus within the other half of the ooplasm could undergo endoreduplication and create an androgenetic cell line. This concept differs from the model suggested by Morales et al. (1) in one decisive point, i.e., a triploid one-cell zygote will not be formed because there is a cytoplasmic division before (not without) replication.

The alternative mechanism of origin for case 1 is based on the assumption that a normally fertilized oocyte fuses with another fertilized but ‘empty’ oocyte. In other words, the second cell is supposed to contain no maternal chromosomes. To the best of my knowledge, there has been no case without chromosomes among the thousands of female gametes that became available for analysis in the course of assisted reproduction (3) and I agree with Golubovsky (4) who already stated that convincing evidence for the existence of anuclear oocytes does not exist.

Morales et al. (1) further mention fertilization of a normal oocyte by a diploid spermatozoon as a third but unlikely possibility. In a previous review I have compiled supportive evidence for this event as a mechanism of origin for diandric triploids (5). A possible restriction, however, is the fact that formation of a diploid paternal pronucleus may mainly occur after intracytoplasmic sperm injection because diploid spermatozoa are particularly found in oligozoospermic men.

Therefore, I wonder whether the cases presented by Morales et al. (1) have resulted from natural conceptions or from assisted reproduction and also, whether a diploid spermatozoon could have played a role in their second case. This would eliminate the necessity of postulating a failure of DNA replication in the female pronucleus followed by normal replication in the embryo.

I appreciate the efforts of Morales et al. (1) who tried to clarify the origin of the observed abnormalities and hope that information obtained from assisted reproduction will serve as a useful contribution.

Bernd E. Rosenbusch, Ph.D.
Department of Gynaecology and Obstetrics
University of Ulm
Ulm, Germany

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.055

References
1. Morales C, Soler A, Badenas C, Rodríguez-Revenga L, Nadal A, Martínez JM, et al. Reproductive consequences of genome-wide paternal uniparental disomy mosaicism: description of two cases with different mechanisms of origin and pregnancy outcomes. Fertil Steril 2009;92:393.e5-e9.

2. Rosenbusch BE, Schneider M. Separation of a pronucleus by premature cytokinesis: a mechanism for immediate diploidization of tripronuclear oocytes? Fertil Steril 2009;92:394.e5-e8.

3. Rosenbusch B. The incidence of aneuploidy in human oocytes assessed by conventional cytogenetic analysis. Hereditas 2004;141:97-105.

4. Golubovsky MD. Postzygotic diploidization of triploids as a source of unusual cases of mosaicism, chimerism and twinning. Hum Reprod 2003;18:236-42.

5. Rosenbusch B. Mechanisms giving rise to triploid zygotes during assisted reproduction. Fertil Steril 2008;90:49-55.

The Authors Respond:

We would like to thank Dr. Rosenbusch for his interest in our article and his comments.

The aim of our paper was to describe two prenatal cases of androgenetic/biparental mosaicism diagnosed in our hospital and review in the literature the most suitable mechanisms of origin in each case. We want to clarify that the different hypotheses proposed have been previously reported by different authors. Moreover, both cases we present have resulted from natural conception, since the couples were never referred for fertility problems.

We agree with Dr. Rosenbusch that in the model of dispermic fertilization of an oocyte in case one, a premature irregular cytokinesis could take place in the oocyte with three pronuclei (one maternal and two paternal), giving rise to a diploid biparental cell and an androgenetic cell. However, premature cytokinesis is considered a very rare abnormality and has only occasionally been seen in unfertilized oocytes (1).

With respect to the existence of “empty” oocytes, it has theoretically been related with the formation of complete moles (2) and it was suggested as a possibility in the model of Surti et al. (3).

Fertilization by a diploid spermatozoon could be a possible scenario. However, this type of event is more frequently related to oligo-crypto-azoospermic males, while normozoospermic individuals produce diandric triploids mainly by dispermy (4).

In summary, multiple hypotheses could be postulated to explain the origin of our cases. We believe that the models we propose are the most probable ones, taking into account that in both cases conception was achieved naturally in couples without fertility problems. As Dr. Rosenbusch states, the description of such cases is essential to clarify the origin of this type of genomic abnormalities.

Carme Morales, Ph.D.
Anna Soler, Ph.D.
Irene Mademont-Soler, Ph.D.
Aurora Sánchez, M.D., Ph.D.
Servei de Bioquímica i Genètica Molecular
Hospital Clínic
Barcelona, Spain

References
1. Rosenbusch BE, Schneider M. Separation of a pronucleus by premature cytokinesis: a mechanism for immediate diploidization of tripronuclear oocytes? Fertil Steril 2009;92:394.e5-8.

2. Fan JB, Surti U, Taillon-Miller P, Hsie L, Kennedy GC, Hoffner L et al. Paternal origins of complete hydatidiform moles proven by whole genome single-nucleotide polymorphism haplotyping, Genomics 2002;79:58-62.

3. Surti U, Hill LM, Dunn J, Prosen T and Hoffner L. Twin pregnancy with a chimeric androgenetic and biparental placenta in one twin displaying placental mesenchymal dysplasia phenotype. Prenat Diagn 2005; 25:1048-56.

4. Egozcue S, Blanco J, Vidal F, Egozcue J. Diploid sperm and the origin of triploidy. Hum Reprod 2002;17:5-7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.054

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