Y chromosome mutations and ICSI; Importance of Y chromosomal and mitochondrial polymorphisms in population genetics Flashcards
infertility facts
can be due to: faillure to conceive, loss of conceptus
origin of problem 35% female 35% male 20% both parters 10% unexplained
semen analysis
volume 1.5-5 ml sperm density >20 million/ml sperm motility >50% sperm moprhology 30% normal forms leukocyte density <1 million/ml
teratospermia
sperms have abnormal morphology or appearance
etiology of male infertility
Varicocele (35-40%) Idiopathic (25%) Infection (~10%) Genetic (~10%) Endocrine (<5%) Cryptorchidism (<5%)
Obstruction (<5%)
Immunologic (<5%)
varicocele
These dilated scrotal veins are present in 16 percent of all men but are more common in infertile men—40 percent. They impair sperm development by preventing proper drainage of blood. Varicoceles are easily discovered on physical examination since the veins feel distinctively like a bag of worms. They may also be enlarged and twisted enough to be visible in thescrotum. This is the most common correctable cause of male infertility.
obstructive azzospermia (OA) clinical features
Normal testicular volume (>15 ml)
Normal serum levels of FSH, LH, testosterone
Normal or reduced semen volume (obstructive)
CBAVD - congenital bilateral absence of vas deferens
Normal testicular biopsy (normal spermatogenesis)
OA etiology
Idiopathic OA Iatrogenic OA (hernia repair, orchidopexy) Infectious (gonorrhea, chlamydia) Traumatic Genetic - CF with CBAVD
genetics and infertility
Genetics play a central role in fertility, particularly since sperm carry half of the DNA mix to the partner’s egg. Abnormalities inchromosomalnumbers and structure as well as deletions on the importantY chromosomepresent in normal males can also impact fertility
non obstructive azoospermia etiology
idiopathic genetic testicular torsion chemo or radiotherapy induced medicaed hormonal deficiency (kallmann's syndrome) anejaculation
human sperm DNA characteristics
highly compacted and packaged with protamines
held together by disulfide bonds
10-15% of sperm have DNA damage
sperm DNA can be modifed by endogenous endonucleases
what are protamines
small,arginine-rich,nuclearproteinsthat replacehistoneslate in thehaploidphase ofspermatogenesisand are believed essential forspermhead condensation andDNAstabilization.
intra-testicular causes for sperm dna damage
protamine P1, P2 deficiency
mutations in the protamine gene cluster
topoisomerase II and transition protein abnormalities (required for repair of induced DNA breaks during super-coiling)
apoptosis
post-testicular or external causes for sperm dna damage
febrile illness semen oxidants (or ROS) can induce sperm DNA damage
cause sperm DNA oxidation and fragmentation in vitro
residual sperm cytoplasm correlates with sperm dna damage
Genetic causes for infertility
Karyotype analysis
Abnormal karyogram in ~3-5% of infertile men (e.g. inversions or
Klinefelter’s 47 XXY);
1-2% of infertile men (2x DAX)
Y- chromosome micro-deletions
7-10% of infertile men vs. ~2% of fertile men
Cystic Fibrosis (CF) gene mutations
Carrier frequency;
~80% in CBAVD (Congenital absence of the vas deferens) vs. ~30% of infertile vs. ~4% fertile men
Kallmann syndrome
MSY
male specific region of Y
99.9% identity
two forms of productive recombination in human y chromosome
X-Y crossing-over in pseudoautosomal regions
Y-Y gene conversion in portions of MSY consisting of nearly identical sequence pairs; palindromes
MSY components
76 protein coding genes
27 distinct proteins
spermatogenic specialization
gene rich palindormes of unprecedented scale and precision
gene conversion and method of preserving gene integrity?
Y chromosome micro-deletions
common cause of male infertility
USP9Y required for sperm production
why is there no sperm production in azoospermia
reasons include: mutations like y deletion radiotherapy chemotherapy mumps orchitis testicular trauma
the spermatogonia cells cannot device
germ cells divison arrest in late stages
ART:
assisted reproduction technology
- compensation for teh impairment of sperm chromatin integity
- transmisison of abnormal genetic material
- current methods for evalulating sperm DNA integrity are not standardized and are not routinely used in clinical laboratories
- to date no treatment for abnormal DNA integirty has proven to be of clinical value
DNA, fertilization, and pregnancy
High levels of sperm DNA damage probably do not affect fertilization or early embryo development
May have an effect on pregnancy rates with advanced reproductive technologies (IVF and IVF/ICSI) and recurrent pregnancy loss with spontaneous conception
Bechwitth Wiedemann syndrome in ART children
5-10 fold higher incidence
same clinical features
same rate in ICSI vs IVF
conclusion of male infertility
Male infertility is multifactorial
Hormones, physiology, environment, anatomy and DNA all play a role
It is the delicate balance of all of these factors that must be weighed in order to optimize male fertility
Every evaluation is different and every treatment strategy is geared toward the individual patient and circumstance and must always take into account the female partner
haplotype
a genetic class described by a series of dna sequences or genes (alleles) that are found together in the same physical chromosomes
