Sex Chromosomes & Disorders Of Development Flashcards
Why is X chromosome inactivation important?
Only one copy of the majority of X chrom genes is necessary
Two copies of some of the genes may be deleterious
What is the biological advantage of sexual reproduction?
It allows the introduction of genetic variation to propagate new genetic traits.
Benefits organisms who:
Exist in a constantly changing environment
Need to fend off disease
Need to purge deleterious mutations
Why are all females considered “functionally mosaic”?
Functional mosaicism results from cells independently inactivating the paternally or maternally derived X chromosome. “Random X inactivation”
What is the role of the XIST gene in X chromosome inactivation?
It is expressed only from the inactivated X, and inactivation cannot occur in its absence. Mechanism is unknown.
When can non-random X chromosome inactivation?
When there is a structurally abnormal X chromosome.
What is “skewed” X inactivation and when is it observed?
Skewed inactivation occurs when one parental X-chromosome is expressed >50% of the time by an unknown mechanism. It is observed when a female shows signs or symptoms of an X-linked recessive trait (Duchene Muscular Dystrophy, Fragile X Syndrome)
Signs, symptoms and karyotype of Turner Syndrome.
45,XO (developmentally female)
Signs at birth:
Prenatal cystic hygroma, Webbed neck, Puffy hands and feet, Heart defects like coarctation of the aorta
Short stature, normal intelligence, infertility
Signs, symptoms, and karyotype of Kleinfelter Syndrome
47,XXY (developmentally male)
Signs in childhood:
Learning disabilities, delayed speech and language, quiet tendency
Tall stature, small testes, reduced facial/body hair, infertility
Signs, symptoms, and karyotype of Jacobs Syndrome
47,XYY (developmentally male)
Learning disabilities, Speech delays, developmental delays
Behavioral and emotional difficulties
Autism spectrum, tall stature
Signs, symptoms, and karyotype of Triple X syndrome
47,XXX (developmentally female)
May have tall stature
Risk of: learning disabilities, delayed speech, delayed motor milestones, seizures, kidney abnormalities
What occurs during primary sex determination?
Gonadal determination is set by the chromosomes. Generally, the presence of a normal Y chromosome results in a male individual, and it’s absence results in a female.
What occurs during secondary sexual determination?
Secondary sexual characteristics are determined by gonads. Includes external or internal genitalia, body habitus, musculature, hair growth, and vocal cartilage.
Two primary male cell lines that develop during the 7th and 8th weeks and their products. What transcription factor is present?
Sertoli cells - Anti-Mullerian Hormone (eventually sperm)
Leydig cells - Testosterone (interstitial cells)
Develop in the presence of SRY
The development of which duct results in male genitalia and which genes are involved?
Mesonephric (Wolffian) duct
SRY, SOX9 - TFs, responsible for production of AntiMullerian Hormone
FGF9 - differentiation of the testes
SF1/NR5A1 - stimulates differentiation of Sertoli & Leydig cells
The development of which duct results in female genitalia and which genes are involved?
Paramesonephric (Mullerian) ducts
WNT4 - differentiates ovaries, inhibited by SOX9
DHH - Up-regulated by WNT4, down regulates SOX9
RSPO1 - Coactivator of WNT pathway
What tests are applicable to disorders of sexual differentiation (DSD)?
1 FISH studies for sex chromosomes and karyotype (poss. microarray)
2 Hormone studies (LH, FSH, testosterone, AMH)
3 Ultrasound study (evaluate for gonads and uterus
4 Surgical consult with urology
What are the karyotype, causes and consequences of androgen insensitivity syndrome?
46,XY
Mutation of X-linked AR (androgen receptor) gene causes inability to recognize testosterone.
Phenotypes range from mild under-virilization to full sex reversal.
What is the karyotype, cause, and consequence of 5-Alpha Reductase deficiency?
46,XY
Mutation of X-linked AR gene (androgen receptor) causes decreased ability to convert testosterone to dihydrotestosterone.
Phenotype shows undervirilized male with increased virilization at the time of puberty.
Three disorders of sexual development associated with the SRY gene.
Deletion or absence of SRY in 46,XY results in phenotypically normal female.
Ectopic presence of SRY in 46,XX results in phenotypically normal male.
Mutations in SRY in 46,XY result in decreased AMH and under virilized male.
Consequences of 21-hydroxylase deficiency
Congenital Adrenal Hyperplasia Ambiguous genitalia in 46,XX Complicated by salt wasting and times of metabolic stress Decreased sodium and chloride Increased potassium
