+

Y Chromosome and Male Infertility

Ana Patrícia Campos (T2) | Ana Margarida Santos (T1)Carolina Soares Aquino (T1) | Joana Direito Abreu (T1)

+Male infertility

Affected processes:

• Hormone release

• Develloping of male organs

• Spermatogenesis

• Sertolli / Leydig cells

• Semen production

• Motility decrease

• Y- associated problems

+Y - Genetic Changes and infertility

Caused by:

De novo mutations

Sex chromosome aneuploidies (2n+1)

Y chromosome microdelections

Partial deletions

Ring chromosome

46, XX male

Gene polymorphisms

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Y Chromosome58 million base pairs; approximately 2% of the total DNA in a male cell.

Contains 86 genes; coding for only 23 distinct proteins.

NRY, with corresponding gene on X chromosome

AZF1 (azoospermiaa factor 1) BPY2 (basic protein on the Y

chromosome) DAZ1 and 2 (deleted in

azoospermia) PRKY (protein kinase, Y-linked) RBMY1A1 SRY (sex-determining region) TSPY (testis-specific protein) USP9Y UTY (ubiquitously transcribed

TPR gene on Y chromosome) ZFY (zinc finger protein) Pseudoautosomal regions

• High mutation rates • The Y chromosome is passed

exclusively through sperm• Sperm are stored in the highly

oxidative environment of the testis.

RISK OF MUTATION 4.8 TIMES GREATER THAN THE REST OF THE

GENOME

+Meiosis, Mitosis and Genetic changesStructural Changes

Intrachromosomal – Y-Y: delection inversion

Interchromosomal – X-Y: translocation

Numeric Changes

Aneuploidy

5 stages:

Leptotene,

Zygotene,

Pachytene,

Diplotene,

Diakinesis

Comparison of meiosis and mitotic cell division. © 2002 by Bruce Alberts, Alexander Johnson, Julian Lewis, Martin

Raff, Keith Roberts, and Peter Walter.

© 2002 by Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter.

© 2002 by Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter.

+A mechanistic model for the divergent outcomes of single and double crossovers between misaligned

sister chromatids (USCE).

Blanco P et al. J Med Genet 2000;37:752-758

+Klinefelter Syndrome

1/500 to 1/1000 males

The karyotype is: 47,XXY (80%) mosaic 46,XY/47,XXY

(20%)

Abnormal number of chromosomes

Non-disjunction in meiosis

+Klinefelter Syndrome Clinical Features

• Abnormal body proportions

• Reduced facial and body hair

• Gynecomastia

• Femal distribution of pubic hair

• Small and firm testicles

• Decreased penis size

• Decreased testosterone levels

• Azoospermia

+Klinefelter Syndrome

Treatment

• Testosterone replacement treatment (as soon as possible)

• Plastic surgery (for gynecomastia)

+Why the Y chromosome?

The Y chromosome is relevant for the study of male infertility

It has several genes involved in spermatogenesis and testicular differentiation

How do we know that?

Development of PCR technique

+PCR(Polymerase Chain Reaction)

(1) DNA’s patterned molecular size

(2) Infertile man without AZF deletions

(3) Infertile man with AZF deletions

(4) Fertile man

(5) WomanElectrophoresis analysis (in agarose gel) of PCR multiple reactions

There were found deletions in the AZF region in 34 out of the 917 men (3,7%) that suffered from azoospermia

or severe oligospermia

+What is the AZF region?

Meiosis arrest

Sertoli cell-only

syndrome

RNA-binding protein(pre-meiotic germ cells)

DAZ(Deleted in

Azoospermia)

Oligospermia

Azoospermia

+Diagnosis

PCR (Polymerase Chain Reaction)

Semen analysis

Testicular biopsy

Cytogenetic analysis (including G-banding and fluorescence in situ hybridization - FISH)

Chromosome microarray (CMA)

+Why is this important?

Different Prognosis

Analysing and Identifying the

mutation

Different mutations

probability of a successful prognosis

Possible to collect semen for

cryopreservation

Infertile man can have children

‘Complete’ forms

‘Incomplete’ forms

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To overcome infertility...

successful mainly for males with deletions in AZFc; rarely for males with deletions in AZFa or AZFb.

due to an autosomal copy - a “back up gene”

The risk for birth defects is the same as any infertile couple who achieves a pregnancy through assisted reproductive technology

In vitro fertilization

using ICSI (intracytoplasmic sperm injection)

+Can Y chromosome infertilitybe inherited? Genetic Counseling

When men with Y chromosome infertility do father children (through assisted

reproductive techniques…)

Usually, Y chromosome infertility prevents men from having children, so this condition is usually caused by de novo mutations

Boys (XY) receive all genetic mutations on the Y chromosome from

their father

Girls (XX) are not affected because they do

not receive any Y chromosome

It is essential to discuss the possibility of transmission of Y chromosome infertility to male offspring in pre-

implantation counseling!

BUT

+Related Genetic Counseling IssuesFamily planning determination of genetic risk to offspring;

discussion of the availability of prenatal testing ;

Presentation of reproductive options.

Analysis of DNA extracted from

fetal cells obtained by

amniocentesis

Information about the sex of the

fetus

Information about the presence of a

Y chromosome deletion.

+

Marchal, J. A.; Acosta, M. J.; Bullejos, M.; de la Guardia, R. D.; Sanchez, A. (2003). Sex chromosomes, sex determination, and sex-linked sequences in Microtidae;

Blanco P., S. M. A. S. C., 2000. Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism, s.l.: Journal of Medical Genetics.

Kauppi L, J. M. K. S., 2012. The tricky path to recombining X and Y chromosomes in meiosis.. [Online]

Available at: http://www.ncbi.nlm.nih.gov/pubmed/22954211 [Acedido em Fevereiro 2013]. Milenkovic T, G.-S. M. Z. D. T. V. L. T. J. G. R. D. L. N., s.d. Molecular Analysis of Y chromosome in a 10

year-old boy with mixed gonadal dysgenesis and growth hormone deficiency, s.l.: Balkan Journal of Medical Genetics.

Plaseska-Karanfilska D, N. P., 2012. Genetic Causes of Male Infertility. [Online] Available at: http://www.bjmg.edu.mk/UploadedImages/pdf/5.pdf

Reijo R., L. T. S. P., 1995. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nature Genetics.

Repping S., S. H. L. J. S. S., s.d. Recombination between Palindromes P5 and P1 on the Human Y Chromosome Causes Massive Deletions and Spermatogenic Failure. [Online] Available at: http://www.cell.com/AJHG/retrieve/pii/S0002929707603747

Sherman J. Silber, M.D, (the Infertility Center of St. Louis), The Y Chromosome and Male Infertility. Available at: http://www.infertile.com/infertility-treatments/y-chromosome.htm

Layman, L. C., 2002. Human Gene Mutations Causing infertility. s.l.:Journal of Medical Genetics. Ferrás, C.; Costa, P.; S. F., F. C., J. M., C. A., M. J. P., C. A., J. S., P. V., S. S., A. G., L. F., M. S., A. B., 2004.

Importância do Estudo das Microdeleções do Cromossoma Y na Infertilidade Masculina, [Online] Available at: http://www.apurologia.pt/acta/4-2004/imp-est-mic-cro-y.pdf Sherman J Silber, MD and Christine M Disteche, PhD. 2013. Y Chromosome Infertility, [Online] Available

at: http://www.ncbi.nlm.nih.gov/books/NBK1339/ ( 27/02/2013) Vogt PH, Bender U., 2013. Human Y chromosome microdeletion analysis by PCR multiplex protocols

identifying only clinically relevant AZF microdeletions, [Online] Availabe at: http://www.ncbi.nlm.nih.gov/pubmed/22992914 Poongothai J., Gopenath T.S., Manonayaki S., 2009. Genetics of human male infertility, [Online] Available at: http://www.ncbi.nlm.nih.gov/pubmed/19421675 Carrasquinho, J.; Coelho, M.; Lourenço, M.; Graça, B. – Sindrome de Klinefelter: Caso Clinico e Revisão

Bibliográfica – Acta Urológica, 2006, 23; 3: 71-74 Esteves, C. Sandro et Agarwal, Ashok – Novel Concepts in Male Infertility – International Brazilian Journal

Urol. – Vol.37 (1). 5-15 Jan-Fev 2011 Kenneth, Jones – Recognizable Patterns of Human Malformation – 5th edition- Smith´s - 2000 – p.72-73 Alberts et al– Biologia Molecular da Célula – 4ªed. Artmed Editora, 2006

Bibliography