Azoospermia factor

Last updated
azoospermia factor 1
Identifiers
SymbolAZF1
Alt. symbolsAZF
NCBI gene 560
HGNC 908
Other data
Locus Chr. Y q11

Azoospermia factor (AZF) is one of several proteins or their genes, which are coded from the AZF region on the human male Y chromosome. [1] Deletions in this region are associated with inability to produce sperm. [2] Subregions within the AZF region are AZFa (sometimes AZF1), AZFb and AZFc (together referred to as AZF2). AZF microdeletions are one of the major causes of male infertility for azoospermia (complete absence of sperm in the ejaculate [3] [4] ) and severe oligozoospermia (less than 5 million spermatozoa in the ejaculate [4] ) males. [5] [6] AZF is the term used by the HUGO Gene Nomenclature Committee.

Contents

Of the 15% of couples who are affected by infertility, 50% of those cases are due to the male partner. [3] 15-30% of male factor infertility cases can be correlated with genetic abnormalities. [5] One of the most commonly identified genetic abnormalities in male factor infertility are microdeletions on the long arm of the Y chromosome (Yq), specifically at a region known as the azoospermic factor (AZF) region. [3]

In certain circumstances, men with AZF mutations can turn to assisted reproductive technologies (ART), such as intracytoplasmic sperm injection (ICSI), to help them overcome their suboptimal sperm quality. However, it may be more important for clinicians to screen for Yq microdeletions, due to a growing body of evidence that AZF microdeletions have the capability to be vertically transmitted to male offspring. [3] [4] [6] Minor et al. demonstrated that an AZFc mutation was vertically transmitted over three generations via fathers receiving reproductive assistance through ICSI. [7]

AZF1 / AZFa

The AZF1 (Azoospermia Factor 1) gene is likely located in the euchromatic part of the long arm in Yq11.23. AZF1 is 792kb long and just distal to the centromere of the Y chromosome. [8] AZF1 genes are involved in spermatogenesis in the testes.

Common phenotypic manifestations of deletions in this region are azoospermia and Sertoli cell-only syndrome. [3] Men with a complete deletion in the AZFa region are unable to produce testicular spermatozoa for ICSI. [4] There are several candidate genes in the AZFa region that have been shown to cause infertility in males: Ubiquitin Specific Peptidase 9, Y-Linked (USP9Y), DEAD Box RNA helices, Box3, Y-linked (DBY), Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-linked (UTY), and Thymosin Beta 4, Y-Linked (TB4Y). [3] [4] [6]

AZF2

Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are sometimes referred to as AZF2.

AZFb

The AZFb subregion is located in the middle region of Yq11. [6] Genes in this region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. [4] Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia. [3] [4] There are multiple candidate genes in the AZFb region that have been shown to cause infertility in males: RNA Binding Motif Protein, Y-linked (RBMY), PTPN13-like, Y-linked (PRY), Chromosome Y Open Reading Frame 15 (CYorf15), Ribosomal Protein S4, Y-linked (RPS4Y1), Eukaryotic Translation Initiation Factor 1A, Y-linked (EIF1AY), Lysine Demethylase 5D (KDM5D), X Linked Kell Blood Group Precursor, Y-linked (XKRY), and Heat Shock Transcription Factor, Y-linked (HSFY). [3] [4] [6]

AZFc

The AZFc subregion is located in the distal part of Yq11. [6] Genes in this region have a diverse role, but overall, they are essential to complete spermatogenesis. [3] [4] AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count. There are multiple candidate genes in the AZFc region that have been shown to cause infertility in males: Deleted in Azoospermia (DAZ), Chromodomain Protein, Y-linked (CDY), and Basic Protein, Y-linked, 2 (BPY2). [3] [4] [6]

AZFc is one of the most genetically dynamic regions in the human genome, possibly serving as counter against the genetic degeneracy associated with the lack of a partner chromosome during meiosis. [9] However, such strategy comes has the adverse effects that some rearrangements represent a risk factor or a de facto causative agent of spermatogenic disruption. [9]

A specific partial deletion of AZFc called gr/gr deletion is significantly associated with male infertility among Caucasians in Europe and the Western Pacific region. [10]

Mutations

Mutations or deletions in the AZF genes are associated with inability or lessened ability to create sperm. It may cause azoospermia (not having any measurable level of sperm in semen). Deletions in the USP9Y gene, which is located within AZF1, are usually associated with inability to form sperm.

See also

Related Research Articles

<span class="mw-page-title-main">Gonad</span> Gland that produces sex cells

A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm in the form of spermatozoa. The female gonad, the ovary, produces egg cells. Both of these gametes are haploid cells. Some hermaphroditic animals have a type of gonad called an ovotestis.

<span class="mw-page-title-main">Intracytoplasmic sperm injection</span> In vitro fertilization procedure

Intracytoplasmic sperm injection is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of embryos that may be transferred to a maternal uterus. With this method, the acrosome reaction is skipped.

<span class="mw-page-title-main">Spermatogenesis</span> Production of sperm

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells.

David C. Page is an American biologist and professor at the Massachusetts Institute of Technology (MIT), the director of the Whitehead Institute, and a Howard Hughes Medical Institute (HHMI) investigator. He is best known for his work on mapping the Y-chromosome and on its evolution in mammals and expression during development. He was cited by Bryan Sykes in Adam's Curse: A Future Without Men.

<span class="mw-page-title-main">Y linkage</span> Traits produced by genes located on the Y chromosome

Y linkage, also known as holandric inheritance, describes traits that are produced by genes located on the Y chromosome. It is a form of sex linkage.

<span class="mw-page-title-main">Azoospermia</span> Medical condition of a man whose semen contains no sperm

Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.

Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility. There has been interest in replacing the descriptive terms used in semen analysis with more quantitative information.

Y chromosome microdeletion(YCM) is a family of genetic disorders caused by missing genes in the Y chromosome. Many men with YCM exhibit no symptoms and lead normal lives. It is present in a significant number of men with reduced fertility. Reduced sperm production varies from oligozoospermia, significant lack of sperm, or azoospermia, complete lack of sperm.

Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

<span class="mw-page-title-main">DAZL</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia-like is a protein that in humans is encoded by the DAZL gene.

<span class="mw-page-title-main">Sertoli cell-only syndrome</span> Medical condition

Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, is defined by azoospermia where the testicular seminiferous tubules are lined solely with sertoli cells. Sertoli cells contribute to the formation of the blood-testis barrier and aid in sperm generation. These cells respond to follicle-stimulating hormone, which is secreted by the hypothalamus and aids in spermatogenesis.

<span class="mw-page-title-main">DAZ1</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene.

<span class="mw-page-title-main">USP9Y</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific peptidase 9, Y-linked , also known as USP9Y, is an enzyme which in humans is encoded by the USP9Y gene. It is required for sperm production. This enzyme is a member of the peptidase C19 family and is similar to ubiquitin-specific proteases, which cleave the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins.

<span class="mw-page-title-main">DAZ3</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia protein 3 is a protein that in humans is encoded by the DAZ3 gene.

<span class="mw-page-title-main">DAZ2</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia protein 2 is a protein that in humans is encoded by the DAZ2 gene.

<span class="mw-page-title-main">DAZ associated protein 1</span> Protein-coding gene in the species Homo sapiens

DAZ-associated protein 1 is a protein that in humans is encoded by the DAZAP1 gene.

<span class="mw-page-title-main">RNA binding motif protein, Y-linked, family 1, member A1</span> Protein-coding gene in the species Homo sapiens

RNA-binding motif protein, Y chromosome, family 1 member A1/C is a protein that in humans is encoded by the RBMY1A1 gene.

<span class="mw-page-title-main">DDX3Y</span> Protein-coding gene in the species Homo sapiens

ATP-dependent RNA helicase DDX3Y is an enzyme that in humans is encoded by the DDX3Y gene.

<span class="mw-page-title-main">BOLL</span> Protein-coding gene in the species Homo sapiens

Protein boule-like is a protein that in humans is encoded by the BOLL gene.

Ann Chester Chandley DSc, F.I.Biol., FRSE was an international cytogeneticist with the Medical Research Council unit which became the Human Genetics Unit at the University of Edinburgh. She became a Fellow of the Institute of Biology in recognition of her contribution and a Fellow of the Royal Society of Edinburgh.

References

  1. ↑ Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, et al. (October 2002). "Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure". American Journal of Human Genetics. 71 (4): 906–22. doi:10.1086/342928. PMC   419997 . PMID   12297986.
  2. ↑ Ioulianos A, Sismani C, Fourouclas N, Patroclou T, Sergiou C, Patsalis PC (June 2002). "A nation-based population screening for azoospermia factor deletions in Greek-Cypriot patients with severe spermatogenic failure and normal fertile controls, using a specific study and experimental design". International Journal of Andrology. 25 (3): 153–8. doi: 10.1046/j.1365-2605.2002.00340.x . PMID   12031043.
  3. 1 2 3 4 5 6 7 8 9 10 O'Flynn O'Brien KL, Varghese AC, Agarwal A (January 2010). "The genetic causes of male factor infertility: a review". Fertility and Sterility. 93 (1): 1–12. doi: 10.1016/j.fertnstert.2009.10.045 . PMID   20103481.
  4. 1 2 3 4 5 6 7 8 9 10 Colaco S, Modi D (February 2018). "Genetics of the human Y chromosome and its association with male infertility". Reproductive Biology and Endocrinology. 16 (1): 14. doi: 10.1186/s12958-018-0330-5 . PMC   5816366 . PMID   29454353.
  5. 1 2 Nailwal M, Chauhan JB (2017). "Azoospermia Factor C Subregion of the Y Chromosome". Journal of Human Reproductive Sciences. 10 (4): 256–260. doi: 10.4103/jhrs.JHRS_16_17 . PMC   5799928 . PMID   29430151.
  6. 1 2 3 4 5 6 7 Yu XW, Wei ZT, Jiang YT, Zhang SL (2015). "Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients". International Journal of Clinical and Experimental Medicine. 8 (9): 14634–46. PMC   4658835 . PMID   26628946.
  7. ↑ Komori S, Kato H, Kobayashi S, Koyama K, Isojima S (2002). "Transmission of Y chromosomal microdeletions from father to son through intracytoplasmic sperm injection". Journal of Human Genetics. 47 (9): 465–8. doi: 10.1007/s100380200066 . PMID   12202984.
  8. ↑ Vogt PH (2005). "AZF deletions and Y chromosomal haplogroups: history and update based on sequence". Human Reproduction Update. 11 (4): 319–36. doi: 10.1093/humupd/dmi017 . PMID   15890785.
  9. 1 2 Navarro-Costa P, Gonçalves J, Plancha CE (March 2010). "The AZFc region of the Y chromosome: at the crossroads between genetic diversity and male infertility". Human Reproduction Update. 16 (5): 525–42. doi:10.1093/humupd/dmq005. PMC   2918367 . PMID   20304777.
  10. ↑ Stouffs K, Lissens W, Tournaye H, Haentjens P (2010). "What about gr/gr deletions and male infertility? Systematic review and meta-analysis". Human Reproduction Update. 17 (2): 197–209. doi: 10.1093/humupd/dmq046 . PMID   20959348.
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