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Y Chromosome and Male Infertility
Ana Patrícia Campos (T2) | Ana Margarida Santos (T1)
Carolina Soares Aquino (T1) | Joana Direito Abreu (T1)
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Male infertility
 Affected
processes:
•
Hormone release
•
Develloping of male organs
•
Spermatogenesis
•
Sertolli / Leydig cells
•
Semen production
•
Motility decrease
•
Y- associated problems
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Y - Genetic Changes and infertility
Caused by:

De novo mutations

Sex chromosome aneuploidies (2n+1)

Y chromosome microdelections
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Partial deletions

Ring chromosome

46, XX male

Gene polymorphisms
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Y Chromosome
 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
58 million base pairs;
approximately 2% of the
total DNA in a male cell.
• High mutation rates
• The Y chromosome is passed exclusively
through sperm
• Sperm are stored in the highly oxidative
environment of the testis.
Contains 86 genes; coding
for only 23 distinct proteins.
RISK OF MUTATION 4.8 TIMES GREATER
THAN THE REST OF THE GENOME
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Meiosis, Mitosis and Genetic changes
Structural Changes
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Intrachromosomal – Y-Y:
 delection
 inversion
Interchromosomal – X-Y:
 translocation
5 stages:
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Leptotene,
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Zygotene,
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Pachytene,
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Diplotene,
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Diakinesis
Numeric Changes
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Aneuploidy
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
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Klinefelter Syndrome

1/500 to 1/1000 males
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The karyotype is:


47,XXY (80%)
mosaic
(20%)
46,XY/47,XXY
Abnormal number of chromosomes
Non-disjunction in meiosis
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Klinefelter Syndrome
Clinical Features
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Abnormal body proportions
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Reduced facial and body hair
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Gynecomastia
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Femal distribution of pubic hair
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Small and firm testicles
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Decreased penis size
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Decreased testosterone levels
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Azoospermia
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Klinefelter Syndrome
Treatment
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Testosterone replacement treatment (as soon as
possible)
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Plastic surgery (for gynecomastia)
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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
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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) Woman
Electrophoresis 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
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What is the AZF region?
DAZ
(Deleted in
Azoospermia)
Meiosis
arrest
RNA-binding protein
(pre-meiotic germ cells)
Sertoli cell-only
syndrome
Oligospermia
Azoospermia
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Diagnosis
 PCR
(Polymerase Chain Reaction)
 Semen
analysis
 Testicular
biopsy
 Cytogenetic
analysis (including G-banding
and fluorescence in situ hybridization FISH)
 Chromosome
microarray (CMA)
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Why is this important?
Different mutations
Different Prognosis
Analysing and Identifying
the mutation
 probability of a
successful prognosis
‘Complete’
forms
‘Incomplete’
forms
Possible to collect
semen for
cryopreservation
Infertile man can
have children
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
To overcome
infertility...
In vitro fertilization
using ICSI
(intracytoplasmic sperm
injection)
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
+ Can Y chromosome infertility
be inherited?
Genetic Counseling

Usually, Y chromosome infertility prevents
men from having children, so this condition
is usually caused by de novo mutations
BUT
When men with Y chromosome infertility do
father children (through assisted
reproductive techniques…)
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!
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Related Genetic Counseling Issues
Family planning

determination of genetic risk to offspring;

discussion of the availability of prenatal testing ;
Analysis of DNA
extracted from
fetal cells obtained
by amniocentesis
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Information about
the sex of the fetus
Presentation of reproductive options.
Information about
the presence of a Y
chromosome
deletion.
Bibliography
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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.
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