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Sex Determination and Sex Chromosomes

Sex Determination and Sex Chromosomes. Harry Ostrer, M.D. Human Genetics Program NYU School of Medicine October 18, 2006. What causes sex differences? What are sex chromosomes doing?. Development of the Embryonic Gonad. Genital ridge. It starts with germ cell migration at 4 weeks.

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Sex Determination and Sex Chromosomes

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  1. Sex Determination and Sex Chromosomes Harry Ostrer, M.D. Human Genetics Program NYU School of Medicine October 18, 2006

  2. What causes sex differences?What are sex chromosomes doing?

  3. Development of the Embryonic Gonad Genital ridge It starts with germ cell migration at 4 weeks Hindgut Metanephric duct Retinoic acid in germ cell environment influences differentiation Sertoli cell – gonocytes (Mitotic arrest) Elsewhere – oogonia (Entry into meiosis) Yolk sac Mesonephros Cloaca

  4. Organization of the Seminiferous Tubule and Ovarian Follicle Spermatozoan Round spermatid Sertoli cell Spematocyte Spermatogonia Peritubularmyoid cells Vascular endothelial cell 1o Oocyte Follicular cells Leydig cells

  5. Development of male and female internal genitalia Seminal vesicle WolffianDucts Vas deferens Metanephros + testosterone Ureter MüllerianDucts Mesonephros Epididymis Gonad + MIF Testis + SRY Fallopian tube WolffianDucts Mullerian duct Wolffian duct Ovary MüllerianDucts Mullerian tubercle Uterus Urogenital sinus Upper third of vagina

  6. tubercle Development of Male and FemaleExternal Genitalia folds tubercle swellings + dihydrotestosterone folds swellings Common Genital Analgen tubercle folds swellings

  7. Expression Of SRY in the Developing Male Embryo 7 wks alk phos antisense sense 9 wks 10 wks 12 wks

  8. 47,XYY 46,XX 47,XXY 47,XXX 48,XXYY 48,XXXX 49,XXXXX 48,XXXY 49,XXXXY Aberrant Sex Chromosome Transmission Usual observation 46,XY 45,X Exceptions  with gonadal dysgenesis 45,X 46,XY  46,XX triploidy with gonadal dysgenesis 69,XXY

  9. SRY SRY Y SRY SRY Y Y X X X Y X Non-homologousRecombination Unequal Recombination Recombinational Models for Individuals with Genetic Sex Reversal 46,XY female 46,XX male

  10. Genes Involved in Male Sex Determination alpha-thalassemia retardation syndrome campomelic dysplasia XH2 SOX9 SRY adrenal failure SF1 DHH 46,XY gonadal dysgenesis WT1 del(2q) Denys-Drash syndrome Frasier syndrome del(9p) del(10q) dupWNT4A dup(X)(p21)

  11. Known Mechanisms of Familial 46,XY Pure Gonadal Dysgenesis Hawkins, 1992 Jager, 1992 Vilain, 1992 SRY I90M binding SRY F109S - nl binding Bilbao, 1996 mosaic Barbosa, 1995 SRY V60L binding mosaic SRY 97C-T truncated protein delSRY Hines, 1997 Schmitt - Ney, 1995 mosaic mosaic b a SRY P125L binding SRY I90M binding SRY 609T-G missense

  12. Genetic Sex Reversal 46,XX True Hermaphrodite

  13. SRY Immunocytochemistry in Familial True Hermaphroditism 82-3951 - newborn TH 85-941 - newborn TH 97-4155 - 14 year TH

  14. Hypothesis: SRY-Bearing Cell Line is Responsible for Testis Development SRY SRY Y-to-X translocation with random X chromosome inactivation 46,XX 46,XX Mosaicism: non-disjunction with post-zygotic loss 47,XXY 47,XXY Chimerism: product of two zygotes 46,XX 46,XY

  15. Organization of Human Sex Chromosomes pseudoautosomal regions (short arms) Many genes escape inactivation Xce – X chromosome inactivation center Length: 153,692,391 bp Gene Count: 1228 sex-limited regions pseudoautosomal regions (long arms) Y Length: 50,286,555 bp Gene Count: 160 X

  16. Why is One X Chromosome Inactivated? Causes Xist (X-inactive specific transcript) expressed from and binds to inactive X chromosome Methylation of specific cytidine residues Late replication Effects Dosage compensation between the sexes mCpG

  17. X-Linked Inheritance Examples: Color blindness Hemophilia Duchenne muscular dystrophy Hypophosphatemic rickets Unaffected parent Carrier parent possible germ cells (egg or sperm) X X Y X possible gametes offspring status Normal daughter Carrier daughter Normal son Affected son 25% 25% 25% 25%

  18. Girl with Duchenne Muscular Dystrophy Delays in sitting and standing Waddling gait Difficulty climbing Rapidly progressive Wheelchair bound by 12 years Cardiomyopathy after age 18 Survival up to third decade Dystrophin staining DMD dystrophin staining

  19. Factors Influencing Expression of X-Linked Phenotypes in Females 45,X chromosomal constitution M Homozygosity for mutant allele M M M M Skewed X chromosome inactivation M M WT WT Selection against cells expressing wild-type gene WT M WT M

  20. 47,XYY 46,XX 47,XXY 47,XXX 48,XXYY 48,XXXX 49,XXXXX 48,XXXY 49,XXXXY Aberrant Sex Chromosome Transmission Usual observation  46,XY 45,X Exceptions with gonadal dysgenesis 45,X 46,XY 46,XX triploidy with gonadal dysgenesis 69,XXY

  21. Turner syndrome Most commonly 45,X Short stature Webbed neck Shield chest Gonadal dysgenesis Coarctation of the aorta Kidney malformation Hypothyroidism Sensorineural hearing loss

  22. Important Structural Abnormalities of the X Chromosome Isodicentric Xq chromosome --> Turner syndrome ring(X) with deletion Xce --> mental retardation and other phenotypic features* dup(X)(p21) --> overexpression of DSS and gonadal dysgenesis in 46,XY individuals* *no X chromosome inactivation

  23. 47,XYY 46,XX 47,XXY 47,XXX 48,XXYY 48,XXXX 49,XXXXX 48,XXXY 49,XXXXY Aberrant Sex Chromosome Transmission Usual observation 46,XY 45,X  Exceptions with gonadal dysgenesis 45,X 46,XY 46,XX triploidy with gonadal dysgenesis 69,XXY

  24. Klinefelter syndrome Most commonly 47,XXY with random X inactivation Hypogonadism (small testes, azoospermia/oligospermia) Hyalinization of seminiferous tubules Gynecomastia at late puberty Psychosocial problems

  25. Triploidy syndrome 69,XXY or 69,XXX Dysmorphic Prematurity Partial mole of the placenta Gonadal dysgnesis, if XXY Die in the early neonatal period

  26. Disorders SRY  gonadal dysgenesis DAZ  azospermia pseudoautosomal region XG pseudoautosomal boundary 0 kb 10 sex-limited region SRY 20 30 Boundary of XX males Genes Genetic Functions CSF2RA IL3RA GCY2 ANT3 ASMT XE7 MIC2R MIC2 XG SRY ZFY p11.3 RPS4Y RBM1 p11.2 TS TSPY (major) AMELY TSPY (minor) p11.1 GBY TS q11.1 XGPY RBM GCY1 KAL q11.21 AZFa RBM1 RBM2 STSp RBM2 q11.22 AZFb SMCY RBM q11.23 RBM1, RBM2 DAZ SPGY AZFc RBM Map of the Human Y Chromosome q12 Y Chromosome

  27. Sex Chromosome Expression in Germ Cells Sperm X and Y inactive during meiosis Some genes reactivated following meiosis Oocytes X chromosome reactivation during oogenesis Deletion of specific regions --> gonadal dysgenesis

  28. Sex Determination and Sex ChromosomesConclusions Sex chromosomes play an important role in sex determination Gene dosage is important with both overexpression and underexpression leading to abnormalities Both sex chromosomes may be subject to inactivation during the course of their life cycle X Y

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