Protamines and Male infertility (student's work)
Protamines and Male Infertility:
1- Definition and Objective:
Infertility is defined as the inability or diminished ability to produce offspring. It is a condition that may be present in either or both partners and is not necessarily irreversible. Our objective behind this simplified research and presentation is to investigate the relation between protamines and male infertility, hoping that uncovering the mystery behind their function would help future generations understand male infertility. We do wish that new researches might find a solution for this issue. So what are Protamines? How are they really organized? And is there any relation between them and male infertility?
To fully understand the utility and significance of protamines, one should start form the building block “What are protamines?”In the following sections we plan to take you through the basic information concerning Protamines and their indispensable functions.
Part One: Basic Knowledge:
1- Discovery and Functions :
Protamines and DNA in male gametes (sperms) were isolated and discovered a century ago by a very eminent scientist, Friedrich Miescher. They are known to be one of the most abundant sperm nuclear proteins in many species, including man, and happen to be responsible for the packaging of the paternal genome. In mammals, including humans, there exists only two types of Protamines: P1 (also known as protamine 1), and the family of protamine 2 (P2), that consists of protamine 2, 3, and protamine 4. In addition to that, recent studies have shown that protamine 1, (P1) is present in all of the vertebrates which have been studied. While P2 on the other hand, is only present in some mammalian species including mice and humans.
Recent and intense studies have been performed in order to discover the significance of protamines and their role in the formation of male gametes also known as spermatogenesis. Based on their questions, many hypothesizes have been postulated regarding this matter and among those a significant number has been proven right. The most obvious and crucial roles of protamines would be:
a- Protamines are a key element in the production of a condensed male gamete with a more compact and hydrodynamic nucleus. And based on what is known and presented from some previous studies, the sperm with the most hydrodynamic structure would move faster than the other sperms and thus fertilizing the first oocyte or ovum. This trait might be then transmitted as an advantage to the future generations if the zygote survives.
b- Some studies state the protamines might play an important role in spermatogenesis and may have a role in whether or not the sperm recognizes the egg and fertilizes it.
After clarifying the importance of protamines and their basic functions in preserving the male gametes, we plan on focusing on their main origin, characteristics and evolution.
2- Origins and Evolutions:
It is important to acknowledge the fact that protamines are proteins which have a remarkably increased number of positively charged residues. The latter fact allows the formation of a well-condensed structure with the male genome which has been proven previously to carry a negative charge. Protamines in addition to that incorporate or integrate Cysteines (Cys) in their sequence. Built on the previous information, this allows the formation of disulfide bonds between protamines molecules facing each other, i.e. protamines molecules bind with each other thus, additionally stabilizing the nucleo-protamine complex (Genome and protamine).
Evidence taken from some studies (1999 and 2006) has concluded that protamines may have evolved from Histone (H1). This conclusion is supported or validated by the fact that protamines possess high rates of evolution. (Studies 1999 and 2006)
3- Organization and localization:
First of all, humans have one copy of PRM1 coding for protamine 1 and another copy of PRM2 coding for protamine 2 (p2). These genes are localized on chromosome number 16, and are organized in the form of a loop with a transition gene TNP2 and gene 4 whose functions are still vague and demands more studies. Some researches would rather consider gene 4 to code for another protamine and would rather call it P3. Yet, gene 4’s predicted amino acid sequence is rich in glutamic acid rather than Argenines which is a recognizable trait in protamines. Hence, you can conclude than it is wrong or misleading to call gene 4 a coder for P3. However, gene 4 and PRM1 and 2 need further studying and research in order to put this long-lasting debate to rest. Further studies on the other hand as expected to answer questions such as: Does gene 4 have an independent function with respect to protamines and other coding genes or is it in any way linked to protamines or male infertility? If yes, then in what manner would that be?
4- Mutations in PRM 1 and PRM2 and Male infertility:
The foremost ambition or objective behind this simplified research as stated in the opening of the presentation is to identify the relation or correlation between male infertility and protamines. The main questions that we hope to answer are: Do alterations or mutations in the genes coding for those protamines in male genome really cause infertility? Is there any significant relation between the ration of protamine1 over protamine 2 and male infertility?
First of all, it is important to understand that all these recent information are still under intensive researches and experimentations. So some facts or conclusions that the research might have deduced lately might be proven wrong later on and vice versa.
Basically, concerning mutations in the coding regions of gene PRM1 and 2 this is all the evidence found and presented for readers:
In Japan 2003, a study was conducted on a group of 226 sterile male patients using 270 proven to be fertile males. After comparing the nucleotide sequence obtained from some patients, the researchers discovered four mutations in the coding region of protamine 1 that was only found in infertile male patients. Among their findings, was a single substitution mutation in p2 gene that caused the appearance of a stop codon that resulted in the execution of translation i.e. premature termination of translation, which would later cause (in some patients) infertility.
The mutation in this case leads to the termination of translation, which would rather lead to the formation of an incomplete protein (protamine) which is probably not functioning. Based on the functions of protamines mentioned earlier, the sperm cell would probably be deformed and this might affect the male gametes and in some studied cases might lead to infertility.
More recently, a study conducted in 2005 showed that a single nucleotide mutation that resulted in the substitution of an Argenine by a Serine in protamine 1 was found in 3 out of 30 infertile male patients. As a result, one of the Argenine groups or clusters was destroyed knocking out one of the most basic elements of Protamines.
The percentage of infertile males with this mutation in the given study is about 10%. It is an important percentage especially in the course of studying such complicated and fragile subject.
The researchers concluded that mutations in protamine during translation are present and might cause infertility in some cases which is infrequent but not as rare as some previous researches thought.
5- Main and Important Studies:
One of the first studies that tried to link male infertility to protamine alteration analyzed protamines in a series of 17 controls (male who were proven fertile) and compared them to seven infertile male patients. The researches detected six out of seven of those patients to have an increase in the ration of p1/p2 with respect to the normal level (1988).
Researches predicted that there might be a link or relation between the ratio p1/p2 and probable male infertility. Similarly, the ratios also differed with patients having abnormal sperm parameter. As a result, they concluded that in normal fertile males, the ratio of p1/p2 is varies slightly. But if it is exceeded it would probably lead to male infertility in some cases, but not all. Researchers found out that there are many reasons behind infertility in males and it is really hard to verify that only protamines might cause infertility for other reasons may collaborate as well.
In 1990, an experiment conducted by researchers concluded that round headed sperms in infertile males (also known to be incapable of fertilizing the ovum), contained less protamines and more histones than normal controls. They concluded that protamines play a significant role in the production of a well condensed sperm which is capable of penetrating the egg or ovum. Others on the other hand, suggested that this is due to the failing to replace histones by protamines during spermatogenesis.
On the other hand, anther independent study on 116 infertile patients shows that about 3.4% (4 out of 116) had a reduction in protamine 2 (1993) while 22.4% of the patients had normal p1/p2 level . This indicates that probably infertility in this group is due to another cause. 7.4% of the patients showed slightly altered p1/p2 ratios. As an explanation, the researchers suggested that this alteration is probably due to the failure in the replacement of histones by protamines in the final stage of spermatogenesis. The detection of an increased number of histones and the decreased proportion of p1/p2 would prove their hypothesis. Similarly, an experiment in 2006, validated the hypothesizes. Its main findings showed that there appear to be an increased number of histones (h2) versus protamines in infertile men.
We can conclude that from the given studies above, infertility in those cases is caused by the same cause explained earlier.
Another experiment was conducted in 2001 in order to understand the role of protamines in fertilization of the oocyte. The experiment uncovered that 12 out of 13 of infertile patients without p2protamine showed a remarkable decrease in the sperm’s penetration assay of an ovum compared to normal male controls with normal P2 levels.
After further studies, the researches confirmed that protamines play a significant role in the fertilization of an ovum and in preserving the human kind. Yet it is pressing to understand that such issues need intensive studies to uncover the true function of protamines.
As a conclusion, protamines are one of the most important nuclear proteins found in the male gametes. Protamines have two types, P1 and the family of P2. Protamines are responsible in the packaging of the male genome. Dense studies have proven that any mutations occurring in the coding regions of the genes responsible in the production of P1 and P2 might lead to different levels of infertility. Also, mutations that cause infertility are infrequent but not rare and in many cases cause infertility in males. Transgenic mice with defected expressions of protamines have showed different distortions in sperm structure.
Yet, this subject demands more studying and future studies are expected to answer questions concerning the true function of protamines. Or” What causes altered levels of protamines to appear? What is the effect of mutations and polymorphisms of protamines expression? How do environmental factors affect these genes and how is it related to male infertility?”
1-Human reproduction Update Advance Access published March 31, 2006: www.scribd.com
2- Taber’s Cyclopedic Medical Dictionary (13th edition) F.A. Davis Company Philadelphia
THis is a student's work...if Infromation are incorrect please help in fixing it... Not a scientific research ....
 Taber’s Cyclopedic Medical Dictionary (13th edition) F.A. Davis Company Philadelphia
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