SS Disorders and Sex Development

MATTERS OF SS
Prepared by:
SAPICO, ABIGAIL M.

In 1937, Alfred Wiskot, a pediatrician in Germany, encountered a family
that had 6 healthy girls, but 3 boys who died of the same illness, at 4,8,
and 18 months. The boys had bruises and skin markings due to poor
clotting, the skin condition eczema, bloody diarhea, ear infections and
pneumonia. All died from bleeding in their digestive tracts and infection in
the blood. Dr. Wiskott noted the inherited nature of the condition and
remarked tht it seemed to affect only boys.

6.1 Sexual DevelopmentSexual Development
●
55thth
weekweek... All embryos develop two
unspecialized gonads.
- Either testes or ovaries.
Each such ''indifferent'' gonad forms near
two sets of ducts that present two
developmental options.

6.1 Sexual DevelopmentSexual Development
●
66thth
weekweek... The choice to follow a male or
female developmental pathway occurs.
- depending upon the sex chromosome
constitution and actions of genes.
MaleMale - if a gene on the Y chromosome called SRY
(sex-determining region of the Y) is activated.
Female – if there's absence of SRY activation.

6.1 sex chromosomessex chromosomes
●
Human males & females have equal number
of chromosomes.
Males- have x and y chromosomes.
Females- have two x chromosomes.
Heterogametic sexHeterogametic sex- w/ 2 different sex chromosomes
Homogametic sexHomogametic sex – w/ 2 same sex chromosomes

6.1 sex chromosomessex chromosomes
X chromosomeX chromosome
- Contains 1,500 genes
- Larger than the Y chromosome
- Acts as a homolog to Y in males
Y chromosomeY chromosome
- Contains 231 genes
- Many DNA segments are
palindromes and may destabilize
DNA

sex chromosomes
Males are the
heterogameti
c sex (XY)
Females are
the
homogameti
c sex (XX)

Anatomy of the Y
chromosome
●
Y chromosome has SRYSRY
(sex-determining region of the Y)
SRYSRY- the master regulator of
maleness
- turns on genes for
production of male
hormones

Y chromosomeY chromosome
●
human Y chromosome is
particularly exposed to high
mutation rates due to highly
oxidative environment of the
testis

6.1 the phenotype formsthe phenotype forms
●
SRY gene encodes a very important
type of protein called transcription
factor.- it stimulates male development by
sending signals to the indifferent
gonads.Sustentacular cells in the testis secrete anti-Mulleriananti-Mullerian
hormonehormone, which destroys potential female structures.
Interstitial cells in the testis secrete testosteronetestosterone, which
stimulates the development of male structures.

Some testosterone is also converted to
dihydrotestosteronedihydrotestosterone (DHT), which directs
development of the urethra, prostate gland,
penis, and scrotum.

Genetic abnormalities can intervine in different points..
For example:
In Androgen InsensitivityAndrogen Insensitivity
SyndromeSyndrome (OMIM 300068)(OMIM 300068), caused by
mutation in X chromosome, the absence
of receptors for androgen, stops cells in
early reproductive structures from
receiving the signal to develop as male.
The person looks female but is XY.

Genetic abnormalities can intervine in different points..
HermaphroditismHermaphroditism- a term for an individual- a term for an individual
with both male and female sexual structures.with both male and female sexual structures.

HermaphroditismHermaphroditism
(the word comes from the Greek god of(the word comes from the Greek god of
war,war, Hermes,Hermes, and the goddess of love,and the goddess of love,
AphroditeAphrodite))

IntersexIntersex- refers to- refers to
individuals whoseindividuals whose
internal structures areinternal structures are
inconsistent withinconsistent with
external structures.external structures.

PseudohermaphroditismPseudohermaphroditism - presence of both types- presence of both types
of structures but at different stages of life.of structures but at different stages of life.

5-alpha reductase deficiency (OMIM5-alpha reductase deficiency (OMIM
264600)264600)--
Affected individuals have SRY gene, normal YAffected individuals have SRY gene, normal Y
chromosome, and testes. Wolffian duct systemchromosome, and testes. Wolffian duct system
persists andpersists and internal maleinternal male reproductive tractreproductive tract
develops. But DHT is deficient and causes the fetusdevelops. But DHT is deficient and causes the fetus
to developto develop externally as femaleexternally as female..

5-alpha reductase5-alpha reductase
deficiencydeficiency

TransgenderTransgender-- has the phenotype and sexhas the phenotype and sex
chromosomes of one gender, but feels extremelychromosomes of one gender, but feels extremely

6.1 is Homosexualityis Homosexuality
inherited?inherited?
HomosexualityHomosexuality - a person's phenotype and- a person's phenotype and
genotype are consistent, and physical attractiongenotype are consistent, and physical attraction
is toward members of the same sex.is toward members of the same sex.

6.1 is Homosexualityis Homosexuality
inherited?inherited?
A team of international researchers has completed a study thatA team of international researchers has completed a study that
suggests we will probably never find a ‘gay gene.' Sexualsuggests we will probably never find a ‘gay gene.' Sexual
orientation is not about genetics, say the researchers, it's aboutorientation is not about genetics, say the researchers, it's about
epigenetics. This is the process where DNA expression isepigenetics. This is the process where DNA expression is
influenced by any number of external factors in the environment.influenced by any number of external factors in the environment.
And in the case of homosexuality, the researchers argue, theAnd in the case of homosexuality, the researchers argue, the
environment is the womb itself.environment is the womb itself.
Documented in 500 animal species

Sexual identity
Level Events Timing
Chromosomal/
genetic
XY= male
XX= female
Fertilization
Gonadal sex Undifferentiated structure begins to
develop as testis or ovary
6 weeks after
fertilization
Phenotypic sex Development of external and internal
reproductive structures continues as
male or female in response to
hormones
8 weeks after
fertilization
Gender
identity
Strong feelings of being male or
female develop
From childhood,
possibly earlier
Sexual
orientation
Attraction to same or opposite sex From childhood

6.1 sex ratiosex ratio
In Mendel's law of segregation, populationsIn Mendel's law of segregation, populations
should have approximately equal numbers of maleshould have approximately equal numbers of male
and female new-borns.and female new-borns.
Sex ratioSex ratio- proportion of males to females in a
human population.
Primary sex ratio – At conception
Secondary sex ratio – At birth
Tertiary sex ratio – At maturity
Sex ratios can change markedly with age

6.1 sex ratiosex ratio
It is interesting to see what happens when a society attempts to alterIt is interesting to see what happens when a society attempts to alter
the sex ratio. This has been done in India and China, wherethe sex ratio. This has been done in India and China, where
researchers have identified great numbers of ''missing females''.researchers have identified great numbers of ''missing females''.
In these societies, prenatal diagnostic techniques are used toIn these societies, prenatal diagnostic techniques are used to
identify XX fetuses. Termination of XX fetuses, underreporting femaleidentify XX fetuses. Termination of XX fetuses, underreporting female
births, and rarely, selective infanticide of girl babies all have contributedbirths, and rarely, selective infanticide of girl babies all have contributed
to a very unnaturaly skewed sex ratio favoring males. In India, theto a very unnaturaly skewed sex ratio favoring males. In India, the
secondary sex ratio fell about 750 girls to every 1,000 boys.secondary sex ratio fell about 750 girls to every 1,000 boys.
At the tertiary ratio in US, people over the age of 65, the sex ratio isAt the tertiary ratio in US, people over the age of 65, the sex ratio is
720. The ratio among older people is the result of disorders that are720. The ratio among older people is the result of disorders that are
more likely to be fatal in males as well as violent activities that maymore likely to be fatal in males as well as violent activities that may
shorten their life span.shorten their life span.

6.2 TraitsTraits Inherited on the SexInherited on the Sex
ChromosomesChromosomes
Y-linkedY-linked – genes carried on Y chromosome.
In females :
2 copies of X-linked = recessive allele
1 copy of X-linked = dominant allele
X-linkedX-linked – genes carried on X chromosome.
In males :
single copy of X-linked = dominant (expression of
trait or illness bec. there's no copy of gene on the 2nd
X chromosome.)

SEXSEX
DETERMINATIONDETERMINATION in
humansAn oocyte has a single X
chromosome. A sperm cell has
either an X or Y chromosome. If
a Y-bearing sperm cell with a
functional SRY gene fertilizes
an oocyte, the zygote is a male
(XY). If an X-bearing sperm
fertilizes an oocyte, the zygote
is a female (XX).

Human male is considered hemizygoushemizygous for X-
linked trait because he has only one set of X-
linked genes.
A male inherits his Y chromosome
from his father and X chromosome
from his mother.
A female inherits one X
chromosome from each parent.

6.2 X-Linked RecessiveX-Linked Recessive
InheritanceInheritance
An X-linked trait passes from an
unaffected heterozygous mother to an
affected son.
Criteria for an X-linked Recessive Trait
1. Always expressed in the male.
2. Expressed in a female homozygote but very rarely in a
heterozygote.
3.Passed from heterozygote or homozygote mother to affected son.
4. Affected female has an affected father and mother who is
affected or a heterozygote.

An X-linked trait
passes from an
unaffected
heterozygous
mother to an
affected son.

A middle-aged man who had
rough, brown, scaly skin did not
realize his condition was inherited
until his daughter had a son.
By a year of age, the boy's skin
resembled his grandfather's.
A test of the daughter's skin
cells revealed that she produced
half the normal amount of enzyme,
indicating that she was a carrier.
IchthyosisIchthyosis

IchthyosisIchthyosis

Hemophilia AHemophilia A

Some Disease-Related Genes on the Human X Chromosome
Lack of certain
antibodies
Agammaglobulinemia (r)Agammaglobulinemia (r)
Alport syndrome (r)Alport syndrome (r)
Deafness, kidney
inflammation

Abnormal tooth enamel
AmelogenesisAmelogenesis
imperfecta (D)imperfecta (D)
Anhidrotic ectodermalAnhidrotic ectodermal
dysplasia(r)dysplasia(r)
No teeth, hair, sweat glands

Skin and lung infections,
enlarged liver and spleen
Chronic granulomatousChronic granulomatous
disease (r)disease (r)
Diabetes insipidus (r)Diabetes insipidus (r)
Copious urination

Progressive muscle weakness
Duchenne muscularDuchenne muscular
dystrophy (r)dystrophy (r) Fabry disease (r)Fabry disease (r)
Abdominal pain, skin
lesions, kidney failure

Vitamin D-resistant rickets
HypophosphateniaHypophosphatenia
(D and r)(D and r)
Lesch-NyhanLesch-Nyhan syndrome (r)syndrome (r)
Mental retardation, self-
mutilation, urinary stones,
spastic cerebral palsy

Enlarged cornea
Megalocornea (r)Megalocornea (r) Menkes disease (r)Menkes disease (r)
Kinky hair, brain degeneration,
abnormal copper transport

Eye degeneration
Norrie disease (r)Norrie disease (r)
Ornithine transcarbamylaseOrnithine transcarbamylase
deficiencydeficiency (rr)(rr)
Mental deteioration,
ammonia in blood

Constriction of visual field,
nightblindness, clumps of
pigment in eye
Retinitis pigmentosaRetinitis pigmentosa
(r and D)(r and D)
Rett syndrome (D)Rett syndrome (D)
Mental retardation,
neurodegeneration

Lack of T and B
lymphocytes
Severe combinedSevere combined
immune deficiency (r)immune deficiency (r)
Wiskott-AldrichWiskott-Aldrich
syndrome (r)syndrome (r)
Bloody diarrhea, infections,
rash, bleeding

6.2 X-Linked DominantX-Linked Dominant
A female who inherits a dominant X-linked allele has
the associated traits or illness, but a male who
inherits the allele is usually more severely affected
because he has only on copy of X-linked allele.
Criteria for an X-linked Dominant Trait
1. Expressed in female in one copy.
2. Much more severe effects in males.
3. High rates of miscarriage due to early lethality in males.
4. Passed from male to all daughters but to no sons.

A newborn girl with IP has
yellow, pus-filled vesicles on her
limbs that come and go over the
1st
few weeks. Then the lesions
become warty to brown splotches
that may remain for life, although
they remain for life.
Males with this condition are
so severely affected that they do
not survive to be born.
Incontinentia Pigmenti (IP)Incontinentia Pigmenti (IP)

Congenital GeneralizedCongenital Generalized
HypertrichosisHypertrichosis
- produces many extra hair
follicles, and hence denser and
more abundant in upper body
hair.
- Hair growth is milder and
patchier in females because of
hormonal differences and the
presence of a second X
chromosome.

6.2 solving a problem:solving a problem:
X-linked InheritanceX-linked Inheritance
(using Mendel's Law of Segregation)(using Mendel's Law of Segregation)
Consider a Kallmann syndrome (OMIM 308700), which causes
very poor or absent sense of smell and small testes or ovaries. It
is X-linked recessive.
Tanisha does not have Kallmann syndrome, but her brother
Jamal and her maternal cousin Malcolm have it. Tanisha's and
Malcolm's parents are unaffected, as is Tanisha's husband Sam.
Tanisha and Sam wish to know the risk that a son would inherit
the condition. Sam has no affected relatives.

6.2 solving a problem:solving a problem:
Steps to follow:
1) Look at the inheritance pattern
2) Draw a pedigree
3) List genotypes & phenotypes and their probabilities
4) Assign genotypes and phenotypes
6) Use Punnett square to determine ratios
7) Repeat for next generation

6.2 solution:solution:
Interpretation:
If Tanisha is a carrier, the probability that their son will
have Kallmann syndrome is 50% or 1 in 2.
(Note that this is a conditional probability. The chance that any
particular son will have the condition is actually 1 in 4, because
Tanisha also has the 50% chance of being genotype XKXK and
therefore not a carrier.)

6.3 Sex-LimitedSex-Limited
andand
Sex-limited traitSex-limited trait -- a trait that affects a
structure or function present in only one sex.
Sex-Influenced TraitsSex-Influenced Traits
Sex-influenced traitSex-influenced trait -- trait is dominant in
one sex but recessive in the other.

6.3 sex-limited traitssex-limited traits
AA sex-limited traitsex-limited trait affects a structure or
function of the body that is present in only
males or only females.

Example:
A New Zeland Cow named Marge, who has a mutation
makes her milk very low in saturated fat, is founding a
commercial herd. Males play their part by transmitting the
mutation, even though they do not make milk.
In humans, beard growth is sex-limited. A woman does
not have beard because she does not manufacture the
hormones required for facial hair growth. She can, however,
pass to her sons the genes specifying heavy beard growth.

Example:
An inherited medical condition that arises during pregnancy is
obviously sex-limited, but the male genome contributes to the
development of supportive structures such as placenta.
This is the case for preeclampsia, a sudden rise in blood
pressure lte in pregnancy. It kills 50,000 women worldwide each
year. If a man's first wife had preeclampsia, his second wife had
double risk of developing the condition, too. Perhaps, a gene
from the father affects the placenta in a way that elevates the
pregnant woman's blood pressure.

6.3 sex-influenced traitssex-influenced traits
In aIn a sex-influenced trait,sex-influenced trait, an allele is
dominant in one sex but recessive in the other.

6.3 sex-influenced traitssex-influenced traits
Pattern baldness is a sex-influenced trait.
Male pattern baldness is related to your genes and male sex
hormones. It usually follows a pattern of receding hairline
and hair thinning on the crown, and is caused by hormones
and genetic predisposition.

6.4 XX
InactivationInactivation
X inactivationX inactivation -- is a process by which one of
the two copies of the X chromosome present in
female is inactivated. The inactive X
chromosome is silenced by its being packaged
in such a way that it has a transcriptionally
inactive structure is called heterochromatin.

6.4 equaling out theequaling out the
sexessexes
Females have two alleles for X chromosome genesFemales have two alleles for X chromosome genes
but males have only onebut males have only one
In mammals, X inactivationX inactivation balances this
inequality and one X chromosome is randomly
inactivated in each cell
The inactivated X chromosome is called a Barr
body

sexessexes
A female is a mosaic forA female is a mosaic for
expression of genes on theexpression of genes on the
X chromosome because ofX chromosome because of
the random inactivation ofthe random inactivation of
either the maternal oreither the maternal or
paternal X in each cell earlypaternal X in each cell early
in prenatal development.in prenatal development.
In anhidroticIn anhidrotic
ectodermal dysplasia, aectodermal dysplasia, a
woman has patches of thewoman has patches of the
skin that lack sweat glandsskin that lack sweat glands
and hair.and hair.

sexessexes
X inactivation occurs early in
prenatal developmen.
A gene called XIST controls
the inactivation. It encodes
an RNA that binds to a
specific site on the (inactive)
X chromosome and
inactivates it.

6.4 effect on theeffect on the
phenotypephenotype
A carrier of an X-linked trait that expressesA carrier of an X-linked trait that expresses
the phenotype is called athe phenotype is called a manifestingmanifesting
heterozygote.heterozygote.
A female who is heterozygous for an X-linked recessive
gene can expressed the associated condition if the normal
allele is inactivated in the tissues that the illness affects.

phenotypephenotype
-- cells that make the enzyme
readily send it to neighboring
cellz essentially correcting the
defect in cells that can't make
the enzyme.
Affected boys are deaf,
mentally retarded, have
dwarfism and abnormal facial
features, heart damage, and
enlarged liver and spleen.
Hunter SyndromeHunter Syndrome
(mucopolysaccharidosis II)(mucopolysaccharidosis II)

phenotypephenotype
-- cells that make the
enzyme readily send it to
neighboring cellz essentially
correcting the defect in cells
that can't make the enzyme.
Affecteentally retarded,
have dwarfism and
abnormal facial features,
heart damage, and enlarged
liver and spleen.
Fabry DiseaseFabry Disease
(alpha-galactosidase A deficiency)(alpha-galactosidase A deficiency)

6.5 Genomic ImprintingGenomic Imprinting
The phenotype of an individual differs depending onThe phenotype of an individual differs depending on
the gene’s parental originthe gene’s parental origin
GenomicGenomic
ImprintingImprinting- a
molecule covers a
gene or several linked
genes and prevents
them from being
accessed to
synthesize protein.

6.5 Genomic ImprintingGenomic Imprinting
MethylMethyl (CH3) groups bind to DNA and suppress
gene expression

6.5 silencing thesilencing the
contributioncontribution
Imprints are erased
during meiosis
- Then reinstituted
according to the sex of
the individual
fromonefromone
parentparent
Figure 6.11

importance ofimportance of GeGenomicnomic
ImprintingImprinting
Imprints are erased during meiosis
- Then reinstituted according to the sex of the
individual
It takes two opposite sex parents to produce a
healthy embryo
- Male genome controls placenta development
- Female genome controls embryo development

Genomic imprinting can explain imcomplete
penetrance, in which an individual is known to have
inherited a genotype associated with a particular
phenotype, but has no signs of the traits.
The predicted genotype is present, but the
associated phenotype is not expressed.

Imprinting may be an important concern in assisted
reproductive technologies that manipulate gametes to
treat infertility.
For example:
Angelman syndrome (OMIM 105830) and Becwith
Wiedemann syndrome (OMIM 130650) are more prevalent
among the offspring of people who used in vitro
fertilization and intracytoplasmic sperm injection to become
pregnant.

6.5 imprintingimprinting Disorders inDisorders in
HumansHumans
Two distinct syndromes result
from a small deletion in
chromosome 15
Prader-WilliPrader-Willi
syndromesyndrome
- Deletion inherited from
father
Angelman syndromeAngelman syndrome
- Deletion inherited from
mother

6.5 imprintingimprinting Disorders inDisorders in
HumansHumans
Increased severity depends on whether it is
inherited from the father or mother or may depend on
uniparental disomyuniparental disomy.
It means ''two bodies from one parent'', and refers
to an offspring who inherits both copies of a gene from
one parent and none from the other.

1. Life stage that is termed secondary ratio.
a. maturity c. birth
b. conception
2. During this week, the choice to follow developmental pathway occurs.
a. 4th
c. 6th
b. 5th
3. The total number of genes in Y chromosome
a. 1,500 c. 231
b. 531
4. The human male with an X and Y chromosomes is called ______________.
a. heterogametic sex c. hemizygous
b. homogametic sex
5. Genes that determines sex and develops along male route.
a. SRY c. DNA
b. DHT

6. Starting about 8 weeks after fertilization, this hormone is secreted which
prevents development of female structures
a. testosterone c. dihydrotestosterone
b. anti-Mullerian hormone
7. It is the term for an individual with both male and female strustures.
a. hermaphroditism c. intersex
b. pseudohermaphroditism
8. A sexual identity that occurs 8 weeks after fertilization or at puberty
a. sexual orientation c. phenotypic sex
b. gender identity
9. It is the trait that is always expressed in males.
a. x-limited trait c. x-linked dominant trait
b. x-linked recessive trait
10. A trait that affects a structure or function of the body that is present in
only males or only females.
a. sex-limited trait c. x-linked trait
b. sex-influenced trait

11. A process by which one of the two copies of the X chromosome present
in female is inactivated.
a. Genomic imprinting c. X-inactivation
b. Equaling out sexes
12. This is the x-inactivated chromosomes.
a. Barr body c. Methyl CH3
b. Protein
13. A carrier of an X-linked trait who expresses the phenotypecarrier of an X-linked trait who expresses the phenotype
a. hemizygous c. heterogametic sex
b. manifesting heterozygote
14. In importance of genomic printing, which genome controls the embyo
development?
a. both male & female genome c. female genome
b. male genome
15. It is a syndrome that is caused by the deletion from the chromosome
inherited from father
a. Prader-Willi syndrome c. Angelman syndrome
b. Wiskott-Aldrich syndrome

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