A healthy volunteer participates in a nutritional research study. After participants ingest a very fatty meal,
serum samples are taken at 1 hour and 3 hours. The diameter of the chylomicrons is measured, showing an
average chylomicron diameter of 500 nm at 1 hour, which decreases to an average diameter of 150 nm at 3
hours. At which of the following locations is the enzyme responsible for this change in chylomicron diameter
most likely present?
Select one:
A. Myocytes
B. Hepatocytes
C. Enterocytes
D. Endothelial cells
E. Adipocytes
A 40-year-old man with a 10-year history of type 1 diabetes mellitus comes to the physician for a routine
examination. He was diagnosed with pancreatitis 25 years ago after a 2-year history of recurrent abdominal
pain. Physical examination shows a thin habitus and abdominal tenderness. After a 12-hour fast, his serum
triglyceride concentration is 4000 mg/dL (normal = 60-140 mg/dL). Intravenous heparin is administered in
order to examine the activity of __________ enzyme.
Select one:
A. Phospholipase C
B. Phospholipase A2
C. Lipoprotein lipase
D. Hepatic lipase
E. Hormone-sensitive lipase
A young boy is brought to his pediatrician with complains of ataxic gait and visual impairments. On physical
examination, the physician finds reduced reflexes in all extremities. Blood biochemistry shows with very low
levels triacylglycerols. Examination of intestinal epithelial cells shows lipid-laden cells. A possible defect leading
to these findings is which of the following?
Select one:
A. Apolipoprotein C-II overexpression
B. LPL deficiency
C. LCAT overexpression
D. MTP deficiency
E. CETP deficiency
What tissues (denoted by a red question mark) are the primary site for the degradation of TAGs carried by
CMs?
Select one:
A. Liver
B. Brain
C. Muscle
D. Adipose tissue
E. Kidneys
What enzyme (denoted by a green question mark) degrades the TAGs?
Select one:
A. Phospholipase A2
B. Pancreatic lipase
C. Adipose lipase
D. Hepatic lipase
E. Capillary lipase
What molecule is the initial acceptor of FAs during TAG synthesis, as shown?
Select one:
A. GAHP
B. Glycerol-3P
C. Glycerol
D. 2-MAG
E. DHAP
A patient told her doctor that a friend told her that if she ate only carbohydrates and proteins and no fats, she
would no longer store fats in adipose tissue. The doctor told the patient her friend was misinformed and then
should further respond to this statement via which one of the following?
Select one:
A. Dietary glucose is converted by the liver into fatty acids and glycerol.
B. Dietary glucose is converted into fatty acids but not glycerol by the liver.
C. Dietary glucose is converted into glycerol but not fatty acids by the liver.
D. Low-density lipoprotein transports the dietary converted products to the muscle tissue for oxidation.
E. Low-density lipoprotein transports the dietary converted products from the liver to the adipose tissue.
Following a high-carbohydrates meal, ATP and NADHH+ levels in cell increase, which inhibits a mitochondrial
enzyme. This results in increased levels of a molecule that will be directed fatty acid synthesis. Which enzyme
is inhibited?
Select one:
A. Alfa-ketoglutarate dehydrogenase
B. Citrate synthase
C. Isocitrate dehydrogenase
D. Pyruvate dehydrogenase
E. Succinyl CoA synthase
A medical student is spending his research year studying the physiology of cholesterol transport within the
body. Specifically, he wants to examine how high density lipoprotein (HDL) particles are able to give other
lipoproteins the ability to hydrolyse triglycerides into free fatty acids. He labels all the proteins on HDL particles
with a tracer dye and finds that some of them are transferred onto very low density lipoprotein (VLDL)
particles after the 2 are incubated together. Furthermore, he finds that only VLDL particles with transferred
proteins are able to catalyze triglyceride hydrolysis. Which of the following components were most likely
transferred from HDL to VLDL particles to enable this reaction?
Select one:
A. Apo-A1
B. Apo-E
C. Apo-CII
D. Lipoprotein lipase
E. Apo-B100
Which of the following statements best distinguishes VLDL from chylomicrons?
Select one:
A. Only VLDL are produced during periods of starvation
B. Only chylomicrons are produced by the liver
C. VLDL have a higher percentage of triglyceride than chylomicrons
D. Only chylomicrons are involved in the delivery of triglyceride to the adipocyte
E. Only chylomicrons contain phospholipids and cholesteryl esters
Pattern of Single Gene Inheritance 1
Basic Concepts
Monogenic (single-gene)traits are known as mendelian traits
More than 16,000 traits or disorders in humans exhibit single gene, monogenic,
unifactorial or mendelian inheritance.
 The 44 autosomes comprise 22 homologous pairs of chromosomes. Each gene
occupies a specific location or locus. The paired autosomal genes have one member
of maternal and the other of paternal origin referred to as alleles.




 Basic Concepts
 Of these 23,000 genes and traits, nearly 21,000 are located on autosomes, more
than 1,200 are located on the X chromosome, and 59 are located on the Y
chromosome.
 A trait or disorder that is determined by a gene on an autosome is said to show
autosomal inheritance, whereas a trait or disorder determined by a gene on one of
the sex chromosomes is said to show sex-linked inheritance.
 Basic Concepts
 The GENOTYPE is the set of alleles that an individual organism possesses.
 A diploid organism with a genotype consisting of two identical alleles is Homozygous
for that locus.
 An organism that has a genotype consisting of two different alleles is
Heterozygous for the locus.
 The term Compound Heterozygote is used to describe a genotype in which two
different/distinct mutant alleles of the same gene are present the locus.
 Basic Concepts
 PHENOTYPE or trait is the manifestation or appearance of a characteristic. It
can refer to any type of characteristic: physical, physiological, biochemical, or
behavioral.
The two (2) Principles of Mendelian Inheritance (Meiosis):
1. The principle of Segregation states that each individual diploid organism
possesses two alleles for any specific trait. These two alleles segregate when
gametes are formed, and one allele goes into each gamete.
2. The principle of Independent Assortment states that genes at different loci are
transmitted independently.
 principle of Segregation
 During the first meiotic division, homologous chromosomes pair. Each chromosome
has an allele for a trait.
 The physical separation of the two chromosomes segregates the alleles from each
other in anaphase
 Each allele will reside in different gametes.
 principle of Independent Assortment
 Principles of Mendelian Inheritance
 Mendel’s law of segregation states the following: The two copies of a gene
segregate (or separate) from each other during transmission from parent to
offspring.
 Mendel’s law of independent assortment states the following: Two different genes
will randomly assort their alleles during the formation of haploid cells. (The
allele for one gene will be found within a resulting gamete independently of whether
the allele for a different gene is found in the same gamete)
 Basic Concepts
 PEDIGREE illustrates the relationships among family members, and it shows which
family members are affected or unaffected by a genetic disease.
 The first person in whom the disease is diagnosed in the pedigree is termed the
Proband or the Index Case or Propositus (proposita for a female).
 A horizontal line connecting a circle and a square represents a mating.
 Basic Concepts
 The extended family depicted in such pedigrees is a kindred
 Brothers and sisters are called sibs, and a family of sibs forms a sibship.
 Couples who have one or more ancestors in common are consanguineous.
 If only one member in a family is affected, he or she is an isolated case. If the
disorder is determined to be due to new mutation in the propositus, a sporadic
case.
 Basic Concepts
 The concept of dominance states that, when two different alleles are present in a
genotype, only the trait encoded by one of them, the “dominant” allele, is observed
in the phenotype.
 FITNESS is defined as the number of offspring affected with the condition who
survive to reproductive age.
 Fitness is not a measure of physical or mental disability. In some disorders, an
affected individual can have normal mental capacities and health but have a fitness
of 0 because the condition interferes with normal reproduction.
 Basic Concepts
 The patterns shown by single-gene disorders in pedigrees depend mainly on two
factors:
1. whether the phenotype is DOMINANT (expressed when one chromosome of
a pair carries the mutant allele and the other chromosome has a wild-type at
that locus) or RECESSIVE (expressed when both chromosomes of a pair
carry mutant alleles at a locus).
2. the CHROMOSOMAL LOCATION of the gene locus, which may be on an
autosome (chromosomes 1 to 22) or on a sex chromosome (chromosomes X
and Y).
 Basic Concepts
 In dominant inheritance a phenotype expressed in both homozygotes and
heterozygotes for a mutant allele is inherited as a dominant.
 In a PURE DOMINANT DISEASE, homozygotes and heterozygotes for the mutant
allele are both affected equally. (rare)
 Dominant disorders are more severe in homozygotes than in heterozygotes, in which
case the disease is called INCOMPLETE DOMINANT (or SEMIDOMINANT).
 Basic Concepts
 PENETRANCE is the probability that a gene will have any phenotypic expression.
When some persons who have the appropriate genotype completely fail to express
it, the gene is said to show Reduced Penetrance.
 EXPRESSIVITY is the severity of expression of phenotype among individuals with
the same disease-causing genotype. When the severity of disease differs in people
who have the same genotype, the phenotype is said to have Variable Expressivity.
 ANTICIPATION occurs in some autosomal dominant and X-linked recessive
disorders where the onset of the disease occurs at an earlier age in the offspring
than in the parents, or the disease occurs with increasing severity in subsequent
generations.
 Basic Concepts
 The relationship between single-gene mutations and disease phenotypes vary
because of GENETIC HETEROGENEITY. This may result from:
1. Different mutations at the same locus termed Allelic Heterogeneity. (e.g.
Cystic Fibrosis CFTR gene)
2. Mutations at different loci termed Locus Heterogeneity (e.g. in Retinitis
pigmentosa 43 loci are responsible for 5 X-linked forms, 14 for autosomal
dominant forms, and 24 for autosomal recessive forms
 Basic Concepts
 Different mutations in the same gene can sometimes give rise to very different
phenotypes. This is called PHENOTYPIC HETEROGENEITY.
 For example, a mutation in the RET gene which encodes a receptor tyrosine kinase
can cause Hirschsprung disease, Multiple Endocrine Neoplasia type 2A and 2B or
both in some individuals .
 Basic Concepts
 PLEIOTROPY: is the term used when multiple phenotypic effects observe from a
single allele or pair of alleles. The term is used particularly when the effects are
seemingly unrelated.
 Basic Concepts
 A PUNNETT SQUARE is a graphical representation of the possible genotypes of
an offspring arising from a specific breeding event.
 It requires knowledge of the genetic composition of the parents.
 The various possible combinations of their gametes are encapsulated in a tabular
format. Each box in the table represents a fertilization event.
 The Punnett Square is a visual representation of Mendelian Inheritance.
 Basic Concept of Probability
 PROBABILITY indicate the likelihood of the occurrence of a specific event. It is
the number of times that an event occurs, divided by the number of all possible
outcomes.
 Probability can be expressed either as a fraction or a decimal number.
 RISK RECURRENCE PROBABILITY, that future children of parents affected by a
genetic disease will also be affected.
 Two rules of probability are useful for predicting the ratios of offspring produced
in genetic crosses. The multiplication rule and the addition rule
 Basic Concept of Probability
 The MULTIPLICATION RULE states that the probability of two or more
independent events occurring together is calculated by multiplying their
independent probabilities
 Suppose a couple wants to know the probability that all three of their planned
children will be girls. Because the probability of producing a girl is 1/2, and because
reproductive events are independent of one another, the probability of producing
three girls is 1/2 × 1/2 × 1/2 = 1/8.
 However, if the couple already has two girls and then wants to know the probability
of producing a third girl, it is simply 1/2. The past events have no effect on the
outcome of the third event.
 Basic Concept of Probability
 The ADDITION RULE states that the probability of any one of two or more
mutually exclusive events occurring and is calculated by adding the probabilities of
these events.
 Mutually exclusive means that one event excludes the possibility of the occurrence
of the other event.
 Imagine that a couple plans to have three children, and they have a strong aversion
to having three children all the same sex. They can be reassured knowing that the
probability of producing three girls or three boys is only 1/8 + 1/8, or 1/4.
 Basic Concept of Probability
 The probability that they will have some combination of boys and girls is 3/4
because the sum of the probabilities of all possible outcomes must add up to 1.
 Basic probability enables us to understand and estimate genetic risks and to
understand genetic variation among populations.
 The multiplication rule is used to estimate the probability that TWO EVENTS
INDEPENDENT WILL OCCUR TOGETHER.
 The addition rule is used to estimate the probability that ONE EVENT OR
ANOTHER WILL OCCUR.
 Autosomal Dominant Inheritance
 Pattern of Inheritance
 An autosomal dominant trait is one that manifests phenotypically in the
heterozygous state.
 Each gamete from an individual with a dominant trait or disorder will contain either
the normal allele or the mutant allele.
 With the dominant mutant allele as ‘D’ and the normal allele as ‘d’. The possible
combinations of the gametes is seen in the image.
 Pattern of Inheritance
 Affected offspring are produced by the union of an unaffected parent with an
affected heterozygote.
 The risk and severity of dominantly inherited disease in the offspring depend on:
1. whether one or both parents are affected
2. whether the trait is strictly dominant or incompletely dominant.
 Features of Autosomal Dominant Inheritance
1. Traits appear in both sexes with equal frequency, and both sexes can transmit
these traits to their offspring.
2. Traits do not skip generations in the pedigree analysis.
 (Exceptions to this rule arise when people acquire the trait as a result of a new
mutation or when the trait has reduced penetrance.
 Features of Autosomal Dominant Inheritance
3. When one parent is heterozygous affected, and the other parent is unaffected 1/2
of the offspring will be affected.
4. When both parents have the trait and are heterozygous, approximately 3/4 of the
children will be affected.
5. Unaffected people do not transmit the trait to their descendants, provided that
the trait is fully penetrant.
 Achondroplasia
 Achondroplasia is the most common cause of human dwarfism. It is an autosomal
dominant disorder caused by specific mutations in FGFR3.
 Two distinct point substitutions account for more than 99% of cases of
achondroplasia.
 Achondroplasia
 The G1138A mutation accounts for 98% of the cases, resulting in a G-to-A DNA
nucleotide point change. The G1138C mutation (1-2%) results from G-to-C DNA
point change.
 The FGFR3 mutations associated with achondroplasia are gain-of-function
mutations.
 Achondroplasia has an incidence of 1 in 15,000 to 1 in 40,000 live births and affects
all ethnic groups.
 Familial hypercholesterolemia (FH)
 This autosomal dominant condition is due to a single mutant gene on the short arm
of chromosome 19.
 This leads to a loss of function in the LDL receptor (LDLR). The LDLR, a
transmembrane glycoprotein is mainly expressed in the liver and adrenal cortex,
plays a key role in cholesterol homeostasis.
 It binds apolipoprotein B-100 and apolipoprotein E, intermediate-density
lipoproteins, and chylomicron remnants.
 Familial hypercholesterolemia (FH)
 Homozygous or heterozygous mutations of LDLR decrease the efficiency of
intermediate-density lipoprotein and LDL endocytosis.
 Accumulation of plasma LDL follows, because of increasing production of LDL from
intermediate-density lipoproteins and decreasing hepatic clearance of LDL.
Ultimately atherosclerosis occurs.
 FH occurs among all races and has a prevalence of 1 in 500 in most white
populations.
 Familial hypercholesterolemia (FH)
 Clinical manifestations include arcus corneae and tendon xanthomas and CAD
(coronary artery disease).
 Incomplete Dominance is seen in FH:
Homozygous FH presents in the first decade with tendon xanthomas and
arcus corneae. If left untreated, death occurs by age 30.
 Heterozygous FH are less severe with arcus corneae and tendon xanthomas
begin to appear by the end of the second decade.
 Neurofibromatosis 1


 NEUROFIBROMATOSIS 1(NF1) is the most common an autosomal dominant
disorder (1:3500)
 It results from mutations in the neurofibromin gene (NF1), located on chromosome
17q.
 It encodes for neurofibromin, which regulates many cellular processes including
activation of Ras GTPase that controls cell proliferation and tumor suppression.
 Neurofibromatosis 1
 Many different mutations have been identified in neurofibromin-1, including
deletions, insertions, duplications, and point substitutions (allelic heterogeneity ).
 Most lead to severe truncation of the protein or complete absence of gene
expression.
 NF1 is characterized by variable expression. No clear genotype-phenotype
correlations have been recognized.
 NF1 is a multisystem disorder with neurological, musculoskeletal, ophthalmological,
and skin abnormalities and a predisposition to neoplasia
 Neurofibromatosis 1
Major Phenotypic manifestations include:
 Age at onset: Prenatal to late childhood
 Café au lait spots
 Axillary and inguinal freckling
 Cutaneous neurofibromas
 Lisch nodules (iris hamartomas)
 Plexiform neurofibromas
 Optic glioma
 Specific osseous lesions
 Neurofibromatosis 1
Principles
• Variable expressivity
• Extreme pleiotropy
• Tumor-suppressor gene
• Loss-of-function mutations
• Allelic heterogeneity
• De novo mutations
 Marfan Syndrome
 Marfan syndrome is a pan-ethnic, autosomal dominant, connective tissue disorder
that results from mutations in the fibrillin 1 (FBN 1)gene located on 15q.
 It has an incidence of approximately 1 in 5000.
 FBN1 encodes fibrillin 1, an extracellular matrix glycoprotein with wide distribution.
Fibrillin 1 polymerizes to form microfibrils in both elastic and nonelastic tissues,
such as the aortic adventitia, ciliary zonules, and skin.
 Marfan Syndrome
 Mutations affect fibrillin 1 synthesis, processing, secretion, polymerization, or
stability.
 The production of mutant fibrillin 1 is a dominant negative pathogenesis causing:
 Inhibition of the formation of normal microfibrils by normal fibrillin 1
 Stimulation of inappropriate proteolysis of extracellular microfibrils.
 Haploinsufficiency also occurs
 Marfan Syndrome
 Marfan syndrome is a multisystem disorder with skeletal, ocular, cardiovascular,
pulmonary, skin, and dural abnormalities.
 The skeletal abnormalities include disproportionate tall stature, arachnodactyly,
pectus deformities, scoliosis, joint laxity, and narrow palate.
 Ocular abnormalities associated with Marfan syndrome are ectopia lentis, flat
corneas, and increased globe length causing axial myopia.
 The cardiovascular abnormalities include mitral valve prolapse, aortic regurgitation,
and dilatation and dissection of the ascending aorta.
Myotonic Dystrophy 1
 Autosomal dominant inheritance with increasing severity in succeeding
generations—anticipation
 A dynamic mutation resulting from CTG repeats in the 3′ UTR region of the DMPK
gene on 19q13.3.
 Disease mutation is 50 to > –2000 repeats
 The DMPK gene provides instructions for making a protein called myotonic
dystrophy protein kinase.
 Clinical manifestation include muscle weakness and wasting
 Myotonia, prolonged muscle contractions and not able to relax certain muscles
after use. For example, a person may have difficulty releasing their grip on a
doorknob or handle
 Cataracts, Cardiac conduction defects
Myotonic Dystrophy 2
 Autosomal dominant disorder caused a tetranucleotide repeat
 A dynamic mutation expansion occurs in intron 1 of CNBP (also known as ZNF9) a
gene on 3q21.3.
 People with type 2 myotonic dystrophy have from 75 to more than 11,000 CCTG
repeats.
PEDIGREE FOR AUTOSOMAL DOMINANT
45
Pedigree for Autosomal dominant
 Autosomal Recessive Disorders
 Autosomal Recessive Inheritance
 Autosomal recessive disease occurs only in homozygotes or compound
heterozygotes
 When a disorder shows recessive inheritance, the mutant allele responsible
generally reduces or eliminates the function of the gene product (a loss-offunction mutation).
 The remaining normal gene copy in a heterozygote can compensate for the mutant
allele and prevent the full phenotypic expression of the disease.
Pattern of Inheritance
 Three types of matings can lead to homozygous offspring affected with an
autosomal recessive disease. The most common mating is between two unaffected
heterozygotes, referred to as Carriers.
 If we represent the normal dominant allele as R and the recessive mutant allele
as r, then each parental gamete carries either the mutant or the normal allele.
 The possible combinations of the gametes is seen in the image.
 Pattern of Inheritance
 75% of the offspring of this mating will not have the disease.
 Of this 75%; 2/3 will be Carriers and 1/3 homozygous normal
 25% of the offspring will be affected and homozygous mutant
 Features of Autosomal Recessive Inheritance
1. Autosomal recessive traits appear with equal frequency in males and females..
2. Affected children inherits two mutant alleles and are commonly born to unaffected
parents who are carriers of the gene for the trait.
3. Whenever both parents are heterozygous, approximately one-fourth of the
offspring are expected to express the trait. The recurrence risk is 1 in 4.
 Features of Autosomal Recessive Inheritance
4. Recessive traits appear more frequently among the offspring of consanguine
matings.
5. In the rare event that both parents are affected by an autosomal recessive trait,
all the offspring will be affected
Cystic Fibrosis
 CYSTIC FIBROSIS is an autosomal recessive disorder incidence is approximately 1
in 2000.
 The gene that encodes the cystic fibrosis transmembrane conductance regulator
(CFTR) protein on 7q. The CFTR protein has ~ 1480 amino acids.
 Most common is the Phe508del (3 base pair deletion which results in the loss of a
phenylalanine residue
 More than 1500 mutations in the CFTR gene have been identified. These include
missense, frameshift, splice site, nonsense, and deletion mutations (allelic
heterogeneity)
 The primary role of the CFTR protein is to act as a chloride channel.
 The net effect of all these mutations is to reduce the normal functional activity of
the CFTR protein,
 Mutant alleles may be handed down from carrier to carrier for numerous
generations without ever appearing in the homozygous state causing overt disease.
 The presence of such hidden recessive genes is not revealed until the carrier mates
with someone who also carries a mutant allele at the same locus and the two
deleterious alleles are both inherited by a child.
 Chronic lung disease caused by recurrent infection eventually leads to fibrotic
changes in the lungs with secondary cardiac failure(Cor Pulmonale).
 Pancreatic dysfunction from blockage of the pancreatic ducts by inspissated
secretions causes malabsorption and steatorrhea.
 Pleiotropy is observed in CF
Sickle Cell Disease
 Sickle cell disease is an autosomal recessive disorder of hemoglobin in which the β
subunit genes have a missense mutation that substitutes valine for glutamic acid at
amino acid 6.
 This mutation occurs on 11p.
 Hemoglobin C (Hb C) is a structural variant of normal hemoglobin A (Hb A) caused
by an amino acid substitution of lysine for glutamic acid at position six of the beta
hemoglobin chain.
 Persons with hemoglobin C trait (Hb AC) are phenotypically normal.
 Those with hemoglobin C disease (Hb CC) have a mild hemolytic anemia (jaundice),
splenomegaly, and borderline anemia due to crystal formation of RBCs
 When a sickle cell carrier and a Hb C carrier mate their progeny are illustrated in
the following pedigree.
 The offspring SC is diseased and will have phenotypical manifestation.
 That offspring is a Compound Heterozygote.
 Sickle cell anemia (homozygosity for HbS) is noteworthy for its PLEIOTROPY
 Approximately 1 in 600 African Americans is born with this disease, which may be
fatal in early childhood, although longer survival is becoming more common.
 The disease occurs most frequently in equatorial Africa and less commonly in the
Mediterranean area and India
Phenylketonuria
 PHENYLKETONURIA (PKU) is an inherited disorder with increased levels of
phenylalanine in the blood due to a deficiency of phenylalanine hydroxylase.
 It is the most common inborn error of amino acid metabolism.
 PKU is caused by mutations in the PAH gene found 12q.
 Phenylketonuria
 The PKU shows allelic heterogeneity.
 Mutations have been described in all 13 exons of the PAH gene and its flanking
region. The mutations types include missense mutations (62% of PAH alleles), small
or large deletions (13%), splicing defects (11%), silent polymorphisms (6%),
nonsense mutations (5%), and insertions (2%).
 PKU displays pleiotropy as well.
Pattern of Single Gene inheritance 2
 Sex Linked Inheritance
 Sex-linked inheritance refers to the pattern of inheritance shown by genes that
are located on either of the sex chromosomes.
 Genes carried on the X chromosome are referred to as being X-linked inheritance.
 Those carried on the Y chromosome are referred to as exhibiting Y-linked or
holandric inheritance.
 Sex Linked Inheritance
 A female has two X chromosomes: one of paternal and one of maternal origin
termed homozygous. Males have only one X chromosome therefore only one copy of
each X - linked gene termed hemizygous.
 In females one of these X chromosomes is inactivated in each somatic cell.
 This mechanism ensures that the quantity of most X - linked gene products
generated in somatic cells of the female is equal to the amount in male cells.
 X - Inactivation
 X inactivation or Lyonization is a normal physiological process in which one of the
two X chromosomes in the female embryoblast is inactivated in the somatic
cells.
 One of the two X chromosomes is randomly chosen for inactivation (i.e. either the
paternal or maternal). That inactive X chromosome remains inactive during
subsequent mitosis of that cell.
 In the trophoblastic cells the paternal X is preferentially inactivated.
 In oogonia the inactive chromosome is reactivated.
 X -Inactivation
As a result of X inactivation, all females have two distinct populations of cells:
One population with a paternally active X chromosome
Another population maternally active X chromosome.
This makes females mosaics for X chromosome activity.
X - Inactivation
X chromosome inactivation begins at a site called the X inactivation center (XIC).
XIST (X inactive specific transcript) gene is located within the XIC.
The RNA produced by XIST gene is highly expressed from the inactive X
chromosome (Xi) during the onset of XCI but not from the active X chromosome
(Xa).
 Xist RNA is an interference RNA (RNAi).

1.
2.
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

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 X - Inactivation
 Xist RNA or RNAi coats the X chromosome and forms an “Xist cloud” over the Xi.
 The Xist cloud acts as a scaffold for the recruitment of silencing factors e.g.
Polycomb repressive complex 2 (PRC2) and DNA methylation.
 X -Inactivation
 Inactive X chromosomes (Xi) during interphase condense into a darkly staining mass
associated with the nuclear membrane called a Barr body.
 The Barr body decondenses during S phase to allow the inactive X chromosome to
be replicated.
 Skewed X inactivation
 In most females the number of cells with either Xi and Xa is roughly equal.
 Dosage equivalency for X-linked genes between XY males and XX females is
achieved.
 However, skewing of X chromosome inactivation is observed in a percentage of
women. This is deviation from equal (50%) inactivation of each parental allele.
 Skewed X inactivation
 Skewed X inactivation is defined as the observation of inactivation of the same
allele in 75% or 80% of cells (and very skewed inactivation resulting in 90% or 95%
of cells with the same allele inactive).
 Skewed X Inactivation
 Skewing of XCI can reflect or result in biological consequences for females.
 Depending on the pattern of random X inactivation of the two X chromosomes, two
female heterozygotes for an X-linked disease can present distinct clinical
manifestation.
 This results from the variation in the proportion of cells that have the mutant
allele on the active X in a relevant tissue.
 X- Linked Inheritance
Dominant
Recessive
X - linked Inheritance
X-linked patterns of inheritance are distinguished based on the phenotype in
heterozygous females.
 Some X-linked phenotypes are consistently expressed in carriers termed
DOMINANT.
 Others that are not typically carrier expressed are RECESSIVE.
 X-linked Recessive
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
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
 Females inherit two copies of the X chromosome and can be:
 Homozygous for a mutant allele at a given locus
 Heterozygous at the locus (mutant and wild-type)
 Homozygous for the normal (wild type) allele at the locus.
 In this way, X-linked loci in females are like autosomal loci. However, X inactivation
leaves only one copy of the allele in an individual somatic cell.
 Half of the cells in a heterozygous female will express the disease allele and half
will express the normal allele. (VARIABLE EXPRESSION)
 X-linked Recessive
 As with autosomal recessive traits, the heterozygote will produce about 50% of the
normal level of the gene product enough for a normal phenotype.
 In males, who are hemizygous for the X chromosome. An inherited recessive gene
on the X chromosome will manifest the disorder.
 The Y chromosome does not carry a normal allele to compensate for the
effects of the disease allele.
 X-linked Recessive
 An X-LINKED RECESSIVE trait (disorder) is one determined by a gene carried on
the X chromosome and usually manifests only in males.
 A male with a mutant allele on his single X chromosome is said to be hemizygous for
that allele.
 In addition, affected males pass this trait to their obligate carrier daughters,
with a consequent risk to male grandchildren through these daughters.
 X-linked Recessive
 Features of X-Linked Recessive Inheritance
 The incidence of traits are higher in males than in females.
 Heterozygous females are usually unaffected.
 The gene responsible for the condition is transmitted from an affected man
through all his daughters.
 Sons of his daughters has a 50% chance of inheriting it.
 features of X-Linked Recessive Inheritance
 The mutant allele is never transmitted directly from father to son.
 The mutant allele may be transmitted through a series of carrier females; affected
males in a kindred are related through these females.
 A significant proportion of isolated cases are due to new mutation
 Duchenne Muscular Dystrophy
 Duchenne muscular dystrophy (DMD,) is X-linked recessive progressive myopathy
caused by mutations within the DMD gene.
 DMD encodes for dystrophin, an intracellular protein that is expressed
predominantly in smooth, skeletal, and cardiac muscle as well as in some brain
neurons.
 In skeletal muscle, dystrophin is part of a large complex of sarcolemma-associated
proteins that confers stability to the sarcolemma.
 Duchenne Muscular Dystrophy
 DMD mutations include large deletions (60% to 65%), large duplications (5% to
10%), and small deletions, insertions, or nucleotide changes (25% to 30%). Allelic
heterogeneity
 Clinical manifestations include muscle degeneration and weakness.
 Begins at the hip girdle muscles and neck flexors, then progresses to involve the
shoulder girdle and distal limb and trunk muscles.
 Male patients usually present between the ages of 3 and 5 years with gait
abnormalities. By 5 years, most patients use a Gowers maneuver and have calf
pseudohypertrophy
 Duchenne Muscular Dystrophy
 By 12 years of age, most patients are confined to a wheelchair and have or are
developing contractures and scoliosis.
 Most die of impaired pulmonary function and pneumonia; the median age at death is
18 years.
 Nearly 95% of patients with DMD have some cardiac compromise (dilated
cardiomyopathy, electrocardiographic abnormalities, or both).
 Duchenne Muscular Dystrophy
 The age at onset and the severity of DMD in females depend on the degree of
skewing of X inactivation.
 If the X chromosome carrying the mutant DMD allele is active in most cells,
females develop signs of DMD; if the X chromosome carrying the normal DMD allele
is predominantly active, females have few or no symptoms of DMD.
 Glucose-6-Phosphate Dehydrogenase Deficiency
 G6PD deficiency is an X-linked recessive disorder caused by mutations in the G6PD
gene.
 G6PD deficiency mutations in the G6PD gene decrease the catalytic activity or the
stability of G6PD, or both.
 G6PD is the first enzyme in the hexose monophosphate shunt, a pathway critical
for generating nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is
required for the regeneration of reduced glutathione.
 Glucose-6-Phosphate Dehydrogenase Deficiency
 Insufficient in NADPH availability leads to reduced regeneration of glutathione
during times of oxidative stress.
 The result is the oxidation and aggregation of intracellular proteins (Heinz bodies)
and the formation of rigid erythrocytes that readily hemolyze.
 Glucose-6-Phosphate Dehydrogenase Deficiency
 The severity of G6PD deficiency depends not only on sex, but also on the specific
G6PD mutation.
 In general, the mutation common in the Mediterranean basin (G6PD B−variant or
Mediterranean) tends to be more severe than those mutations common in Africa
(G6PD A− variants).
 G6PD deficiency most commonly manifests as either neonatal jaundice or acute
hemolytic anemia.
 Viral and bacterial infections are the most common triggers, but many drugs and
toxins can also precipitate hemolysis.
 Glucose-6-Phosphate Dehydrogenase Deficiency
 The disorder called favism results from hemolysis secondary to the ingestion of
fava beans by patients with more severe forms of G6PD deficiency, such as G6PD
Mediterranean.
 Fava (broad) beans contain β-glycosides, a naturally occurring oxidants.
 Lesch - Nyhan Syndrome
 Lesch-Nyhan disease is caused by mutations in the HPRT gene on the X
chromosome.
 Hypoxanthine-guanine phosphoribosyl transferase (HPRT) plays a key role in the
recycling of the purine bases, hypoxanthine (inosine) and guanine, into the purine
nucleotide pools
 The mutations are heterogeneous, with more than 600 different ones documented,
including single base substitutions, deletions, insertions, or substitutions. Allelic
heterogeneity
 Lesch - Nyhan Syndrome
 In the absence of HPRT, purine bases are not salvaged but degraded and excreted
as uric acid.
 Uric acid production increase with subsequent hyperuricemia.
 Hyperuricemia increases the risk of uric acid crystal precipitation in the tissues to
form tophi.
 In addition to failed purine recycling, the rate of purine synthesis is accelerated to
compensate for purines lost in the salvage process.
 Lesch - Nyhan Syndrome
LNS is associated with 3 major clinical elements:
 OVERPRODUCTION OF URIC ACID – characterized by nephrolithiasis with renal
failure, gouty arthritis, and solid subcutaneous deposits known as tophi
 NEUROLOGIC DISABILITY – dominated by dystonia but may include
choreoathetosis, ballismus, spasticity, or hyperreflexia.
 BEHAVIORAL PROBLEMS – include intellectual disability aggressive and impulsive
behaviors (persistent self- injurious behavior).
 X – Linked Dominant
 In X-linked dominant disorders manifest in the heterozygous female and
hemizygous males with the mutant allele on his single X chromosome.
 Both the daughters and sons of an affected female have a 1 in 2 (50%) chance of
being affected.
 An affected male transmits the trait to all his daughters but to none of his sons.
 There is no male-to-male transmission.
 Features of X-Linked Dominant Inheritance
 Both male and female offspring of female carriers have a 50% risk of inheriting the
phenotype.
 Both males and females (heterozygous) can be affected.
 Affected females are about twice as common as affected males but have milder
expression of the phenotype.
 X – linked Dominant
 Fragile X Syndrome
 Fragile X syndrome is an X-linked disorder of intellectual disability that is caused
by mutations in the FMR1 gene on Xq27.3
 The FMR1 gene product is expressed in many cell types but most abundantly in
neurons. The FMRP protein chaperone a subclass of mRNAs from the nucleus to the
translational machinery.
 FMR1 dynamic mutations are expansions of a (CGG)n repeat sequence in the 5′
untranslated region (UTR) of the gene.
 Fragile X Syndrome
 In normal alleles of FMR1, the number of CGG repeats ranges from 6 to about 50.
 In disease-causing alleles or full mutations, the number of repeats is more than
200.
 Alleles with > 200 CGG repeats usually have hypermethylation of the CGG repeat
sequence and the adjacent FMR1 promoter which leads to inactivation (silencing)
and loss of FMRP expression.
 Fragile X Syndrome
 Mutable alleles (~ 59 to 200 CGG repeats) occurs from maternal transmission of a
mutant FMR1 allele.
 Mutable alleles are often shortened with paternal transmission.
 Full mutations do not arise from normal alleles.
 The severity of the phenotype depends on repeat length mosaicism and repeat
methylation (Anticipation)
 Fragile X Syndrome
 Fragile X syndrome causes moderate intellectual disability in affected males and
mild intellectual deficits in affected females.
 Most affected individuals also have behavioral abnormalities, including
hyperactivity, hand flapping or biting, temper tantrums, poor eye contact, and
autistic features.
 Characteristic features include a long narrow face, large ears, a prominent jaw and
forehead, unusually flexible fingers, flat feet and in males, enlarged testicles
(macroorchidism) after puberty become more apparent with age.
 X-linked hypophosphatemia
 X-linked hypophosphatemia (XLH) is a dominant disorder and accounts for more
than 80% of all familial hypophosphatemia.
 This loss of function mutation of the phosphate-regulating endopeptidases on the
X chromosome (PHEX), leads to low levels of phosphate in the blood
(hypophosphatemia).
 The gene product zinc-metallopeptidase is responsible for the catabolism and
circulatory clearance of fibroblast growth factor-23 (FGF23).
 X-linked hypophosphatemia
 FGF23 acts on the kidney to cause increased phosphate excretion and decreased
alpha-1 hydroxylase activity.
 The resulting over activity of this FGF23 reduces phosphate reabsorption by the
kidneys, leading to hypophosphatemia and the related features.
 Symptoms become apparent within the first 18 months of life, when a child begins
to bear weight on the legs.
 X-linked hypophosphatemia
 Clinical manifestations include
 Abnormal bone development (leading to bowing or twisting of the lower legs)
and short stature or a slowing growth rate.
 Abnormal tooth development
 Bone pain, muscle pain and weakness
 Rett Syndrome
 Rett syndrome is an X-linked dominant disorder with a female prevalence of 1 in
10,000 to 1 in 15,000.
 It is caused by loss-of-function mutations of the MECP2 gene.
 MECP2 encodes a nuclear protein that binds methylated DNA and recruit histone
deacetylases to regions of methylated DNA.
 Its dysfunction is believed to cause inappropriate activation of target genes
because of failed gene repression (silencing)
 Rett Syndrome
 Classic Rett syndrome is a progressive neurodevelopmental disorder occurring
almost exclusively in girls.
 After apparently normal development until 6 to 18 months; a short period of
developmental slowing and stagnation with decelerating head growth
 Loss of speech and acquired motor skills follows.
 They develop stereotypic hand movements, breathing irregularities, ataxia, and
seizures.
 Alport Syndrome
 Alport syndrome refers to a group of inherited, heterogeneous disorders
involving the basement membranes of the kidney and affecting the cochlea and
eye.
 These disorders are the result of mutations in type IV collagen genes which is the
major constituent of the GBM (glomerular basement membrane).
 The alpha-5 (IV) and alpha-6 (IV) chains are encoded by
genes COL4A5 and COL4A6, respectively, on the X chromosome
 Alport Syndrome
 Three (3) genetic forms of Alport syndrome exist (LOCUS HETEROGENEITY):
 XLAS - Results from mutations in the COL4A5 gene; accounts for 85% of
cases of Alport syndrome
 Autosomal recessive Alport syndrome (ARAS) caused by mutations in
the COL4A3 or COL4A4 gene; responsible for ~10-15% of cases
 Autosomal dominant Alport syndrome (ADAS) is rare; caused by mutations in
the COL4A3 or COL4A4
 Alport Syndrome
 Phenotypical expression is characterized by kidney disease, hearing loss, and eye
abnormalities.
 Renal manifestations include hematuria, proteinuria and hypertension
 Sensorineural hearing loss
 Ocular manifestations include anterior lenticonus, dot and flecks retinopathy
and posterior polymorphous corneal dystrophy
 Y-Linked Inheritance
 The Y chromosome approximately 60 Mb of DNA, contains relatively few genes.
 These gene
 Initiates differentiation of the embryo into a male,
 Several genes that encode testis specific spermatogenesis factors,
 A minor histocompatibility antigen (termed HY)
 Several housekeeping genes, which all have inactivation escaping homologues
on the X chromosome.
 Y-Linked Inheritance
 Transmission of Y-linked traits is strictly from father to son.
 A mutation on the DFNY1 gene can cause hearing loss.
 This Y-linked deafness-1 (DFNY1 gene) is characterized by male-limited post lingual
progressive sensorineural hearing loss of variable severity, with onset in the first
to third decades of life.
 Pedigree and Probability assessment
 Pedigree Analysis
 The following pedigree represents the inheritance of a rare disorder in an
extended family. What is the most likely mode of inheritance for this disease?
(Assume that the trait is fully penetrant.)
 Pedigree Analysis
The pedigree that includes individuals with Charcot-Marie-Tooth disease (CMT). A
neurologic disorder that produces dysfunction of the distal extremities with
characteristic foot-drop. Which of the following patterns of inheritance is depicted in
this pedigree?
A. Autosomal Dominant
B. Autosomal Recessive
C. X-linked Dominant
D. X-linked Recessive
E. Mitochondrial
 Risk recurrence
If individual III-4 becomes pregnant, what is her risk of having a child with CMT?
A. 1/2
B. 1/4
C. 1/8
D. 1/16
E. Virtually 0
The predominance of affected males with transmission through females makes this
pedigree diagnostic of X-linked recessive inheritance. Individual I-1 is an obligate
carrier, seen by her affected son and grandson.
Individual II-2 cannot transmit an X-linked disorder, his daughters are obligate carriers.
Individual II-3 is a carrier indicated by her affected son. There is a ¼ probability of
recurrence of CMT in her offspring.
 Risk Recurrence
Individual III-4 also has a ½ probability of being a carrier with ¼ (25%) of having an
affected offspring like her mother.
½ x ¼ = ⅛ probability of III-4
 MCQ
A couple from rural Pennsylvania with their four children. Both the parents have normal
complexion with brown hair. Of the four children, 2 have brown hair and fair skin, and 2
have white hair and skin and light blue eyes. Physical examination of the 2 lighter children
(black circle and square in the pedigree shown) shows strabismus and nystagmus. Which
of the following is the probability that IV-3 is a carrier of the trait?
A. 1/4
B. 1/3
C. 1/2
D. 2/3
E. 1/1
 Pedigree Analysis
A
a
A
AA
Aa
a
Aa
aa
 Autosomal recessive inheritance shows a pattern of skipping generations with
unaffected parents having affected children as illustrated in the pedigree.
 the pedigree also reflects consanguineous mating prevalent in autosomal recessive
disorders.
 Albinism is an autosomal recessive disorder generally characterized by a defect in
the tyrosinase enzyme. This leads to the inability to produce melanin.
► The Punnett square shows the frequency of genotypes of offspring for two
heterozygous parents.
► There is 25% (¼)chance of normal, 50% (½) of carriers and 25% (¼) of affected.
► Since IV-3 and IV-4 are unaffected and not included in the 25% affected.
► Therefore IV-3 and IV-4 are among remaining 75% (¾). There is also a 50% (½)
chance of IV-3 being a carrier.
Probability of IV-3 being a carrier is:
50% (0.5) ÷ 75% (0.75) =66% (0.66)
OR
4
4
½ ÷ ¾ = ½ x /3 = /6= ⅔
Ans: D
 Risk recurrence assessment
 Based on the given pedigree what is the probability that IV-2 will manifest traits
for this autosomal recessive disease?
 Risk recurrence assessment
 III-2 is a carrier and has a ½ or 50% chance of passing the mutant allele to IV -2
 III-3 has a ½ or 50% chance of being a carrier and has a ½ or 50% chance passing
the mutant allele to IV-2
½ x ½ x ½ = ⅛
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