A Tetragametic Woman

27 April 2014 by Joe Dramiga, posted in Uncategorized

A case report by Yu, et. al. in The New England Journal of Medicine narrates the discovery of a tetragametic woman; that is a woman derived from four different gametes, not just two.

The 52-year-old came to the doctors' attention because she suffered from focal sclerosing glomerulonephritis and needed a kidney transplant. In preparation for kidney transplantation, she and her immediate family underwent a histocompatibility antigen blood test.

The Histocompatibility Antigen Blood Test

A histocompatibility antigen blood test looks at proteins called human leukocyte antigens (HLAs). These are found on the surface of almost all cells in the human body. HLAs are found in large amounts on the surface of white blood cells. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.

The HLA Complex

The HLA complex is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. In humans, the MHC complex consists of more than 200 genes located close together on chromosome 6. Genes in this complex are categorized into three basic groups: class I, class II, and class III.

Humans have three main MHC class I genes, known as HLA-A, HLA-B, and HLA-C. The proteins produced from these genes are present on the surface of almost all cells. On the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from within the cell.

MHC class I proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct. HLA genes have many possible variations, allowing each person's immune system to react to a wide range of foreign invaders.

Some HLA genes have hundreds of identified versions (alleles), each of which is given a particular number (such as HLA-B27). Closely related alleles are categorized together; for example, at least 40 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2743.

The Results of the Histocompatibility Antigen Blood Test

1. The histocompatibility antigen test showed her to have inherited the "1" HLA region of her father (who was 1, 2) and the "3" region of her mother (who was 3, 4).

2. She had two brothers,

a)one who inherited 1 from their father and 3 from their mother
b)the other who inherited 2 from their father and 3 from their mother.

3. Her husband typed 5, 6.

4. Of her three sons,

a)One was 1,6 which was to be expected,
b)but the other two were both 2,5. The 5 they got from their father, but where did the 2 come from?

The doctor’s first thought was that she could not have been their mother, but clearly she knew better.
A clue came from typing other tissues. PCR analysis of her skin cells, hair follicles, thyroid cells, bladder cells, and cells scraped from inside her mouth revealed not only 1 and 3 but also 2 and 4. It is not clear why her bone marrow was an exception - containing only 1, 3 stem cells.

How were these Test Results possible?

The most reasonable explanation is that her mother had simultaneously ovulated two eggs: one containing a chromosome 6 with HLA 3; the other with HLA 4.

Her father would, of course, have produced equal numbers of 1-containing and 2-containing sperm.

*A 1-sperm fertilized the 3-egg
*A 2-sperm fertilized the 4-egg.

Soon thereafter the resulting early embryos fused into a single embryo. As this embryo developed into a fetus, both types of cells participated in constructing her various organs including her oogonia (but not, apparently, the blood stem cells in her bone marrow). Although she was a mosaic for the HLA (and other) genes on chromosome 6, all her cells were XX. So both the father's successful sperm cells had carried his X chromosome.

tetragameticwoman
Figure Proposed Derivation of Various Tissues in the tetragametic woman. The findings were based on the results of PCR analysis. Both cell lines are represented to some extent in all tissues except blood.

So What are her Chances for Finding a Suitable Kidney Donor?

Ordinarily, there is only a 1 in 4 chance that two siblings share the same transplantation antigens if both parents were heterozygous as in her case. But because this woman has all four sets of transplantation antigens, she can accept a kidney from any one of her brothers as well as her mother (her father was dead) without fear of rejecting it. Laboratory tests confirmed that she was unable to generate T cells able to react against the cells of either brother or her mother.

Journal Reference

Disputed maternity leading to identification of tetragametic chimerism. Yu N, Kruskall MS, Yunis JJ, Knoll JH, Uhl L, Alosco S, Ohashi M, Clavijo O, Husain Z, Yunis EJ, Yunis JJ, Yunis EJ. N Engl J Med. 2002 May 16;346(20):1545-1552.

Picture Credits

Yu et al., N Engl J Med. 2002 May 16;346(20, 1545-1552: Figure 4, Page 1551

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