Lecture 14: Disorders of Sexual Development

what are disorders of sexual development (DSD)?

- Conditions resulting in discordance between genetic, gonadal, or anatomic sex (internal & external structures) -> intersex individuals

- DSD result from mutations of any of the genes involved in typical sex development or differentiation

- Adequate expression of these genes & proper timing of their expression is important

Ambiguous genitalia

-infant's genital phenotype (external genitals) do not appear to be clearly either male for female

-they used to do surgery straight after birth, often to female but now they need patient consent as there would be long term consequence for affected individuals.

- intersex

SRY translocation

The SRY is located adjacent to the PARS region.

• this is the region on the X and Y chromsome that undergoes crossing over during meiosis.

• in some rare cases the SRY locus is translocated onto an X chromosome during crossover.

• If this sperm containing this translocation fertilises an oocyte → the karyotype will not match the phenotypic expression.

  • genetically female but phenotypically male.

XX male syndrome

- Female karyotype: 46, XX

- no Y chromosome, so genetically female

- Offspring who inherit the SRY gene on the X chromosome (or translocation to an autosome)

- Formation of both testicles and ovaries in the same individual

- No MIF produced so female internal duct structures present

Swayer Syndrome

- Male karyotype 46, XY

- Y chromosome present, so genetically male

- Y chromosome has accidentally lost the SRY region in crossing over, or gene encoding TDF is mutated making it non-functional

- If no active SRY gene, which encodes TDF, development into a phenotypical female occurs , even though person is genetically male

- Testes hidden in abdominal cavity and a female phenotype

androgen insensitivity syndrome (AIS)

- Male karyotype 46, XY

- Functional SRY gene: TDF expressed, but can have outwardly female phenotype due to an underlying androgen insensitivity syndrome (AIS)

- Testes develop, testosterone is secreted but target cells lack receptors for the androgens - no masculinizing effects occur

- SRY has been shown to interact with the androgen receptor

- Female body type and gender identity but sterile

• individuals can have complete or partial AIS

testosterone deficiency

- Male karyotype 46, XY

- Functional SRY region: TDF expressed, MIF expressed

- Can have female phenotype due to Leydig cells in testes not secreting testosterone

- Internal structures and gonads will develop into male structures, but the external genitalia will be female

-> no masculinizing effects occur

- Individuals are sterile and will not go through puberty

5-a-reductase deficiency

- remember, 5-a-reductase-2 acts on testosterone to produce dihydrotestosterone (DHT)

- Male karyotype 46, XY

- Functional SRY region: TDF expressed, MIF expressed, but a 5-α-reductase deficiency

- so, levels of dihydrotestosterone (DHT) very low

- Male internal structures and gonads

- Born with female phenotype or ambiguous genitalia depending on levels of DHT

mullerian inhibiting substance deficiency

- If mutated gene for Mullerian Inhibiting Substance

- Mullerian female ductal structures will not regress

- External genitalia will be male due to presence of testosterone

- Affected individuals usually sterile because testes do not develop normally, and presence of female ducts interferes with sperm transport

True Cryptorchidism

- Absence of one or both testes from the scrotum

- Undescended testicle in 3-4% of boys

- Spermatogenesis: Production of viable sperm, is greatly affected by the temperature of the testicle

- Untreated: Risk of infertility, testicular torsion, cancers

sex determination in Drosophila melanogaster

- seen in the species Drosophila melanogaster

- Y chromosome doesn't carry factors for maleness, so sex is determined by the amount of X chromosomes

- XY = males

- XX = females

- X0 = sterile males

- XXY = females

what is the X0 sex determination system?

- seen in arachnids

- there is only one sex chromosome, the X chromosome (there are no Y chromosomes)

- Sperm of male normally contains either one X chromosome or no sex chromosomes at all

- X0 = male

- XX = female (hermaphrodite)

there are two phenotypes possible:

- male: only has testes, five pairs of autosomes, one single X chromosome

- hermaphrodite: has both testes and ovaries, five pairs of autosomes and two X chromosomes

ZW sex determination system

- in birds

- sex chromosomes are Z and W

- male: homogametic, ZZ

- female: heterogametic, ZW

how can the environment determine sex in species?

reptiles

- In some reptiles, environmental factors determine sex of progeny

- there are no discernible sex chromosomes, nor is their sex determined by the presence or absence of specific genes

- Thermosensitive period of sex development (so, temperature determines the sex)

- Higher temperatures: exponential increase in aromatase activity

• aromatase : an enzyme that is responsible for the conversion of androgens into estrogens’s

- Different levels of aromatase activity guide differentiation of the indifferent gonad into an ovary or testis

turtles:

- Eggs incubated above 32°C develop into females

- Eggs below 28°C become male

- Eggs between 28°C-32°C develop into either sex

Alligators

• Eggs incubated below 30°C all females

• Eggs incubated above 34°C all males

• Temperature sensitive period days 7-21

• Natural sex ratio 5 females : 1 male

Haplodiploid genetic system - Parthenogenesis

- In insects (e.g. Hymenoptera), unfertilized eggs develop into uniparental haploid males, whereas fertilized eggs into biparental diploid females

- E.g. Ants, bees, wasps

sex change in species

- Female sexual characteristics are substituted for male ones (or vice versa) during lifetime

- Sex change may occur naturally as part of sequential hermaphroditism

- Protandrous hermaphrodites: Organisms that are born male and at some point in their lifespan change sex to female e.g. clown fish

- Protogynous hermaphrodites: Organisms that are born female and at some point in their lifespan change sex to male