Sex chromosome anomalies
Prenatal development
• Chromosome sex established at fertilisation
• At 6 weeks, 46XX and 46XY have same organs – undifferentiated gonads developed from genital ridges
lying on the side of interim kidneys
• Important to determine when looking at sex development disorders
• Steroidogenic factor gene (SF1) on chromosome 9 encodes a nuclear receptor associated with
hormone production
• Wilms tumour suppressor protein 1 (WT1) on chromosome 11p active in development of gonads and
kidneys
• 2 primitive ducts – male-like Wolffian ducts, female-like Mullerian ducts
• Externally, both embryos have genital tubercle and urogenital groove surrounded by folds and swelling
• Both male and female ducts, derived from mesonephrons, are present in a 6-week embryo
Male development and sex differentiation
• At 7 weeks, SRY gene on chromosome Yp produced protein testis-determining factor (TDF) – this
triggers inner part of gonadal ridges to develop into testis
• Other X-linked and autosomal genes necessary for differentiation of testis – e.g., SOX9 (homeobox)
gene on chromosome 17
• Foetal testis begin to secrete 2 hormones
o Anti-mullerian hormone (AMH) causes Mullerian ducts to regress – AMH in chromosome 19q
functions only in presence of Y chromosome, activity regulated by SF1 product
o Testosterone produced to maintain Wolffian ducts which form prostate gland, seminal vesicles
and vas deferens
o Dihydrotestosterone (DHT), derived from testosterone, organises shaping of external genitals
(conversion catalysed by 5-reductase – penis and scrotum formed
• SRY regulation in mouse model
o Epigenetic modifiers, transcription factors and kinases involved in SRY regulation
o Model assembles all known regulators into 3 modules, each converging on a single transcription
factor that binds SRY promoter (for normal functioning)
• Genome wide analysis
o Activation of SRY initiates testis development
o SRY is a transcription factor – a protein complex (including SRY) binds to a SOX9 enhancer
element
o SOX9 interactions with other elements causes male sex determination to occur and testis
development
o 4 patients with 46XX, testicular disorders who where SRY-negative
▪ Compared loss of heterozygosity (LOH) and CNV to normal female control data
▪ LOH induced 27 genes in 19 regions of 11 chromosomes
▪ CN loss included 55 genes in 13 regions of 10 chromosomes
▪ CN gain in 6 regions of 4 chromosomes, including upstream region of SOX3 located in
Xq27.1 (non-coding region)
▪ Likely that CN gain led to high expression of SOX3 causing testicular development,
despite no SRY
• Defects in testosterone synthesis
o Can have mutation at any stage of synthesis which is defective
o Variety of different sex developmental disorders depending on synthesis stage defect occurs
Female development and sex differentiation
, • Occurs in absence of male development
• Products of several genes causes parts of genital ridges to develop into ovaries at 12 weeks
• DAX1 plays key role – encodes nuclear hormone receptor related to SF1 and functions as anti-testis
gene by opposing effect of SRY
• Other X-linked and autosomal loci required
• 2 X chromosomes required for ovarian maintenance
• Wolffian ducts regress in absence of testosterone
• Mullerian ducts form female ducts, in absence of AMH
• Forward parts from fallopian tubes, end parts fuse to form uterus and vagina
• External genitalia fail to fuse and clitoris forms from genital tubercle and labia from surrounding
folds
• Undifferentiated gonads develop into ovaries in absence of normal SRY expression
• X chromosome inactivation
o Mary Lyon (1961) suggested hypothesis for dosage compensation regarding genes on X
chromosome
o In females, an X chromosome is randomly inactivated during embryogenesis – inactivation is
irreversible so same X chromosome is inactive in all daughter cells (i.e., all somatic cells)
o In some cells, maternal X is inactivated and in other cells paternal X is inactivated so females
are mosaic regarding active X chromosome
o Not all genes on inactive X chromosome are inactivated (genes escape)
o X inactivation controlled by X-inactivation specific transcript (XIST) gene which produces a
poly-adenylated RNA which acts to initiate cascade of events leading to inactivation
o Barr (1949) observed heterochromatin in nuclear periphery of many cells – correlates to
number of inactive X chromosome
o Buccal smears used to examine Barr bodies in infants with ambiguous genitals (now
replaced with FISH
▪ No Barr body = normal male, female with turner Syndrome (45X)
▪ 1 Barr body = normal female, 47XXY male
▪ 2+ Barr body = aneuploidy
o Only 1 active X chromosome per cell (no matter how many X chromosome there are)
o Methylation of Barr body
• Methylation inactivates X chromosome
• Methylation seen using immuno-FISH analysis
Sex chromosome anomalies – won’t be asked exam question on specific disorder, but could be asked to
give overview of main disorders with attention on Turner and Klinefelter syndrome
Y chromosome – phenotypically male
X chromosome – phenotypically female
Turner Syndrome – 45,X
• Liveborn incidence 1 in 5000 female births
• Ultrasound detect generalised oedema or swelling localised to neck
• Symptoms include
o Webbing of neck
o Under 5 foot tall (short statue)
o Normal intelligence
o SHOX gene haploinsufficiency
o Streak ovary results in primary amenorrhoea and infertility
o Coarctation of aorta in 15% of cases
• Diagnosis suggested in newborn by redundant neck skin and peripheral lymphoedema
Prenatal development
• Chromosome sex established at fertilisation
• At 6 weeks, 46XX and 46XY have same organs – undifferentiated gonads developed from genital ridges
lying on the side of interim kidneys
• Important to determine when looking at sex development disorders
• Steroidogenic factor gene (SF1) on chromosome 9 encodes a nuclear receptor associated with
hormone production
• Wilms tumour suppressor protein 1 (WT1) on chromosome 11p active in development of gonads and
kidneys
• 2 primitive ducts – male-like Wolffian ducts, female-like Mullerian ducts
• Externally, both embryos have genital tubercle and urogenital groove surrounded by folds and swelling
• Both male and female ducts, derived from mesonephrons, are present in a 6-week embryo
Male development and sex differentiation
• At 7 weeks, SRY gene on chromosome Yp produced protein testis-determining factor (TDF) – this
triggers inner part of gonadal ridges to develop into testis
• Other X-linked and autosomal genes necessary for differentiation of testis – e.g., SOX9 (homeobox)
gene on chromosome 17
• Foetal testis begin to secrete 2 hormones
o Anti-mullerian hormone (AMH) causes Mullerian ducts to regress – AMH in chromosome 19q
functions only in presence of Y chromosome, activity regulated by SF1 product
o Testosterone produced to maintain Wolffian ducts which form prostate gland, seminal vesicles
and vas deferens
o Dihydrotestosterone (DHT), derived from testosterone, organises shaping of external genitals
(conversion catalysed by 5-reductase – penis and scrotum formed
• SRY regulation in mouse model
o Epigenetic modifiers, transcription factors and kinases involved in SRY regulation
o Model assembles all known regulators into 3 modules, each converging on a single transcription
factor that binds SRY promoter (for normal functioning)
• Genome wide analysis
o Activation of SRY initiates testis development
o SRY is a transcription factor – a protein complex (including SRY) binds to a SOX9 enhancer
element
o SOX9 interactions with other elements causes male sex determination to occur and testis
development
o 4 patients with 46XX, testicular disorders who where SRY-negative
▪ Compared loss of heterozygosity (LOH) and CNV to normal female control data
▪ LOH induced 27 genes in 19 regions of 11 chromosomes
▪ CN loss included 55 genes in 13 regions of 10 chromosomes
▪ CN gain in 6 regions of 4 chromosomes, including upstream region of SOX3 located in
Xq27.1 (non-coding region)
▪ Likely that CN gain led to high expression of SOX3 causing testicular development,
despite no SRY
• Defects in testosterone synthesis
o Can have mutation at any stage of synthesis which is defective
o Variety of different sex developmental disorders depending on synthesis stage defect occurs
Female development and sex differentiation
, • Occurs in absence of male development
• Products of several genes causes parts of genital ridges to develop into ovaries at 12 weeks
• DAX1 plays key role – encodes nuclear hormone receptor related to SF1 and functions as anti-testis
gene by opposing effect of SRY
• Other X-linked and autosomal loci required
• 2 X chromosomes required for ovarian maintenance
• Wolffian ducts regress in absence of testosterone
• Mullerian ducts form female ducts, in absence of AMH
• Forward parts from fallopian tubes, end parts fuse to form uterus and vagina
• External genitalia fail to fuse and clitoris forms from genital tubercle and labia from surrounding
folds
• Undifferentiated gonads develop into ovaries in absence of normal SRY expression
• X chromosome inactivation
o Mary Lyon (1961) suggested hypothesis for dosage compensation regarding genes on X
chromosome
o In females, an X chromosome is randomly inactivated during embryogenesis – inactivation is
irreversible so same X chromosome is inactive in all daughter cells (i.e., all somatic cells)
o In some cells, maternal X is inactivated and in other cells paternal X is inactivated so females
are mosaic regarding active X chromosome
o Not all genes on inactive X chromosome are inactivated (genes escape)
o X inactivation controlled by X-inactivation specific transcript (XIST) gene which produces a
poly-adenylated RNA which acts to initiate cascade of events leading to inactivation
o Barr (1949) observed heterochromatin in nuclear periphery of many cells – correlates to
number of inactive X chromosome
o Buccal smears used to examine Barr bodies in infants with ambiguous genitals (now
replaced with FISH
▪ No Barr body = normal male, female with turner Syndrome (45X)
▪ 1 Barr body = normal female, 47XXY male
▪ 2+ Barr body = aneuploidy
o Only 1 active X chromosome per cell (no matter how many X chromosome there are)
o Methylation of Barr body
• Methylation inactivates X chromosome
• Methylation seen using immuno-FISH analysis
Sex chromosome anomalies – won’t be asked exam question on specific disorder, but could be asked to
give overview of main disorders with attention on Turner and Klinefelter syndrome
Y chromosome – phenotypically male
X chromosome – phenotypically female
Turner Syndrome – 45,X
• Liveborn incidence 1 in 5000 female births
• Ultrasound detect generalised oedema or swelling localised to neck
• Symptoms include
o Webbing of neck
o Under 5 foot tall (short statue)
o Normal intelligence
o SHOX gene haploinsufficiency
o Streak ovary results in primary amenorrhoea and infertility
o Coarctation of aorta in 15% of cases
• Diagnosis suggested in newborn by redundant neck skin and peripheral lymphoedema
