Azoospermia factor

Azoospermia factor (AZF) refers to 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.

azoospermia factor 1
Identifiers
SymbolAZF1
Alt. symbolsAZF
NCBI gene560
HGNC908
Other data
LocusChr. Y q11

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 common 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 is becoming increasingly 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

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.

AZFa

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]

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
"AZFc" redirects here. For the Dutch football club, see AZ Alkmaar.

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]

AZF2

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

AZF 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 but not always associated with inability to form sperm.

See also

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. 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. 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. 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. 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. 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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