Prof.

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Lecture 1
PRINCIPLES OF MOLECULAR DISEASES (part I)
From monogenic diseases to a comparison between simple and complex diseases.

The effects of pathogenic variants on the phenotype

Both these situations can have different effects on

gene functions. Some mutations affect expression
(reduction of complete failure of expression) or they
can cause overexpression.
They can also cause the production of an altered
protein, that can either result in a lack of function or in
an altered functions.

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 LOSS OF FUNCTION:
 Complete expression
failure;
 Reduction in
expression.
 GAIN OF FUNCTION (overexpression
leading to an increased copy
number); the altered gene product:
o Lacks the normal function;
o Has an altered or new
function.

Nomenclature to describe an allele:

 NULL ALLELE / AMORPH: an allele
that produces no product.
 HYPOMORPH: an allele that produces a reduced amount or activity of the product.
 HYPERMORPH: an allele that produces an increased amount or activity of the product.
 NEOMORPH: an allele that produces a product with a novel activity.
 ANTIMORPH: an allele that produces a product with an activity that antagonizes the activity of the normal
product (dominant negative effect).

For most genes, the precise quantity of product is not critical. We can deal with half of the actual production.

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---***---

LOSS OF FUNCTION: examples

Congenital Adrenal Hyperplasia
(loss of function: recessive condition)

In the most common form, insufficient synthesis of cortisol is accompanied with excessive production of male sex
hormones. This condition results in a reduction of the synthesis of glucocorticoids and mineralocorticoids.
Ambiguous genitalia in girls due to high concentration of testosterone during development. Hyperpigmentation of
genitalia in boys.

Deficiency of an enzyme: 21-hydroxylase.

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There are various forms of this disease:

1. Severe (classical) phenotype: the residual enzymatic
activity varies between 0% and 11% (usually < 2%).
2. Mild (non-classic) phenotype: the residual enzymatic
activity is between 20 and 50%.

When the enzymatic activity is > 10%, the disease form is so

mild, that it is usually diagnosed later in life.

In this disease the relationship between phenotype and

genotype is very clear: the enzymatic activity depends on the
kind of mutation in a very strict way.

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Why is this mutation so frequent?

This gene is located on the p arm of chromosome 6. This region is prone to rearrangements, it is an unstable
genomic region.

Both the CYP21A2 gene and the CYP21AP pseudogene lie in the Major Histocompatibility Complex at chromosome
6p21.3, which is a complex organization of genes.

There is a 90% homology between gene and pseudogene (the pseudogene is the one that doesn't work, so it
accumulates lots of mutations - negative selection).

WIKIPEDIA: PSEUDOGENE

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Pseudogenes are functionless relatives of genes that have lost their gene expression in the cell or their ability to code
protein. Pseudogenes often result from the accumulation of multiple mutations within a gene whose product is not
required for the survival of the organism. Although not protein-coding, the DNA of pseudogenes may be functional,
similar to other kinds of noncoding DNA which can have a regulatory role.
Although some pseudogenes do not have introns or a promoter (these pseudogenes are copied from messenger RNA
and incorporated into the chromosome and are called processed pseudogenes), most have some gene-like features
such as promoters, CpG islands, and splice sites. They are different from normal genes due to a lack of protein-coding
ability resulting from a variety of disabling mutations (e.g. premature stop codons or frameshifts), a lack of
transcription, or their inability to encode RNA (such as with ribosomal RNA pseudogenes).
Because pseudogenes are generally thought of as the last stop for genomic material that is to be removed from the
genome, they are often labeled as junk DNA. A pseudogene can be operationally defined as a fragment of nucleotide
sequence that resembles a known protein's domains but with stop codons or frameshifts mid-domain. Nonetheless,
pseudogenes contain biological and evolutionary histories within their sequences. This is due to a pseudogene's
shared ancestry with a functional gene: in the same way that Darwin thought of two species as possibly having a
shared common ancestry followed by millions of years of evolutionary divergence, a pseudogene and its associated
functional gene also share a common ancestor and have diverged as separate genetic entities over millions of years.

Segmental duplication: this genomic regions are similar and induce non allelic rearrangements.

The recombination between the pseudogene and the functioning gene results in the inactivation of the normal gene
(unequal pairing or chromosomal exchange or gene conversion).

WIKIPEDIA: SEGMENTAL DUPLICATION

Segmental duplications (SDs) are segments of DNA with near-identical sequence.
Segmental duplications give rise to low copy repeats (LCRs) (highly homologous sequence elements within the
eukaryotic genome, typically 10–300 kb in length with >95% sequence identity) and are believed to have played a
role in creating new primate genes as reflected in human genetic variation. In humans, chromosomes Y and 22 have
the greatest proportion of SDs: 50.4% and 11.9% respectively.
Misalignment of LCRs during non-allelic homologous recombination (NAHR) is an important mechanism underlying
the chromosomal microdeletion disorders as well as their reciprocal duplication partners. Many LCRs are
concentrated in "hotspots", such as the 17p11-12 region, 27% of which is composed of LCR sequence. NAHR and non-
homologous end joining (NHEJ) within this region are responsible for a wide range of disorders, including Charcot–
Marie–Tooth syndrome type 1A, hereditary neuropathy with liability to pressure palsies, Smith–Magenis syndrome
and Potocki–Lupski syndrome.

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Usually the pseudogene is the "donor" of the new sequence and the normal gene is the "acceptor": when this
happens we have the formation of an heteroduplex condition.

Mismatch repair enzymes recognize this sequences.

If we compare the normal gene with and without the mutation we see that the mutations on the normal gene are
sometimes identical to the sequence of the pseudogene.

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If the two mutations are in cis (one mutation from the mother and one from the father) we have a carrier; if they
are in trans (both mutations from one parent) the individual is affected. To understand this, we have to check the
parents.

However, the disease can be:

1. MONOMODULAR
2. BIMODULAR
3. TRIMODULAR

This is the frequency in Caucasian population.

Haploinsufficiency results in the pathologic phenotype (loss of function).

WIKIPEDIA: HAPLOINSUFFICIENCY
Haploinsufficiency is a mechanism of action to explain a phenotype when a diploid organism has lost one copy of a
gene and is left with a single functional copy of that gene. The genotypic state in which one of two copies of a gene
is absent is called hemizygosity. Hemizygosity is not the same as haploinsufficiency; hemizygosity describes the
genotype, and haploinsufficiency is a mechanism that may have caused the phenotype. The general assumption is
that the single remaining functional copy of the gene cannot provide sufficient gene product (typically a protein) to
preserve the wild-type phenotype leading to an altered or even diseased state. As such, hemizygosity is typically
transmitted with dominant inheritance, either autosomally or X-linked in female humans.
Dominance describes the circumstance in which both alleles in a diploid organism are present but one allele is
responsible for the phenotype. That genotypic state is one of heterozygosity (with two different alleles).
Co-dominance is that situation where the effects of both alleles are apparent in the phenotype.

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Waardenburg syndrome type I

(loss of function: dominant condition)

WIKIPEDIA: PAX3 GENE

PAX3 is a gene that belongs to the paired box (PAX) family of transcription factors. It has been identified with ear, eye
and facial development. Mutations in it can cause Waardenburg syndrome types 1 and 3. It is expressed in early
embryonic phases in dermatomyotome of paraxial mesoderm which it helps to demarcate. In that way PAX3
contributes to early striated muscle development since all myoblasts are derived from dermatomyotome of paraxial
mesoderm.
All the mutations have a loss of function effect, but with different degrees.

WIKIPEDIA: WAARDENBURG SYNDROME

Waardenburg syndrome is a rare genetic disorder most often characterized by varying degrees of deafness, minor
defects in structures arising from the neural crest, and pigmentation changes.
Symptoms vary from one type of the syndrome to another and from one patient to another, but they include:

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 Very pale or brilliantly blue eyes, eyes of two different colors (complete heterochromia), or eyes with one iris
having two different colors (sectoral heterochromia);
 A forelock of white hair (poliosis), or premature graying of the hair;
 Appearance of wide-set eyes due to a prominent, broad nasal root (dystopia canthorum) - particularly
associated with Type I) also known as telecanthus;
 Moderate to profound hearing loss (higher
frequency associated with Type II);
 A low hairline and eyebrows that meet in the
middle (synophrys);
 Patches of white skin pigmentation, in some cases;
 Abnormalities of the arms, associated with Type III;
 Neurologic manifestations, associated with Type IV.
Waardenburg syndrome has also been associated with a
variety of other congenital disorders, such as intestinal and
spinal defects, elevation of the scapula and cleft lip and
palate. Sometimes this is concurrent with Hirschsprung
disease.

This condition is usually inherited in an autosomal

dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In most cases, an
affected person has one parent with the condition. A small percentage of cases result from new mutations in the
gene; these cases occur in people with no history of the disorder in their family.
Some cases of type II and type IV Waardenburg syndrome appear to have an autosomal recessive pattern of
inheritance, which means two copies of the gene must be altered for a person to be affected by the disorder. Most
often, the parents of a child with an autosomal
recessive disorder are not affected but are carriers of
one copy of the altered gene.

Genomic disorders
RANDOM WEBSITE: GENOMIC DISORDERS
Genomic disorders are diseases that result from the
loss or gain of chromosomal/DNA material. The most
common and better-delineated genomic disorders are
divided in two main categories: those resulting from
copy number losses (deletion syndromes) and copy
number gains (duplication syndromes).

Copy number variations

Structural genetic variation refers to a class of sequence alterations spanning more than 1000 bases (one kilobase or
kb). This class includes quantitative variations such as copy number variations (CNVs), sequence rearrangements
(such as those observed among immunoglobulins), and other less common variations, including chromosomal
rearrangements that may or may not alter the genome contents and in some cases result in disease.

CNVs, the most prevalent type of structural variation, are DNA segments spanning thousands to millions of bases
whose copy number varies between different individuals. These submicroscopic genomic differences in the number of
copies of one or more sections of DNA are the result of DNA gains or losses. Copy number gains can be the result of
duplications, triplications, or even multiple copy number gains. Most deletions are one copy loss (heterozygous), but
in some instances the loss can affect both copies (homozygous deletions).
CNVs are most commonly inherited but can occur de novo. These were initially thought to be rare events resulting
from sporadic mutation and correlated with specific Mendelian diseases. Advances in technology have shown that
deviation from the diploid state is widespread and contributes substantially to genetic diversity.

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In the picture on the right- sopra:

 SMS: Smith-Magendie Syndrome
 PWS: Prader-Willi Syndrome
 AS: Angelman Syndrome
 WBS: Williams-Buren Syndrome

Angelman syndrome
(variants affecting indirectly multiple genes)
WIKIPEDIA: ANGELMAN SYNDROME

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Angelman syndrome is a neurodevelopmental disorder characterized by severe intellectual and developmental
disability, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling and
usually a happy demeanor.
AS is a classic example of genomic imprinting: it is caused by deletion or inactivation of genes on the maternally
inherited chromosome 15, while the paternal copy, which may be of normal sequence, is imprinted and therefore
silenced. The sister syndrome, Prader–Willi syndrome, is caused by a similar loss of paternally inherited genes and
maternal imprinting. An older, alternative term for AS, "happy puppet syndrome", is generally considered
stigmatizing. People with AS are sometimes referred to as "angels", both because of the syndrome's name and
because of their youthful, happy appearance.

Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most
commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or
single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from the mother,
the other from the father. However, in the region of the chromosome that is critical for Angelman syndrome, the
maternal and paternal contribution express certain genes very differently. This is due to sex-specific epigenetic
imprinting; the biochemical mechanism is DNA methylation. In a normal individual, the maternal allele of the gene
UBE3A, part of the ubiquitin pathway, is expressed and the paternal allele is specifically silenced in the developing
brain. In the hippocampus and cerebellum, the maternal allele is almost exclusively the active one. If the maternal
contribution is lost or mutated, the result is Angelman syndrome. The methylation test that is performed for
Angelman syndrome (a defect in UBE3A) looks for methylation on the gene's neighbor SNRPN (which is silenced by
methylation on the maternal copy of the gene).

While Angelman syndrome can be caused by a single mutation in the UBE3A gene, the most common genetic defect
leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing
an absence of UBE3A expression in the paternally imprinted brain regions. UBE3A codes for an E6-AP ubiquitin ligase,
which chooses its substrates very selectively, and the four identified E6-AP substrates have shed little light on the
possible molecular mechanisms underlying Angelman syndrome in humans.

Prader-Willi syndrome
(variants affecting directly multiple genes)

WIKIPEDIA: PRADER-WILLI SYNDROME

Prader–Willi syndrome (PWS) is a genetic disorder due to loss of function of specific genes on
chromosome 15. In newborns symptoms include weak muscles, poor feeding and slow
development. In childhood the person becomes constantly hungry which often leads to
obesity and type 2 diabetes. There is also typically mild to moderate intellectual impairment
and behavioral problems. Often the forehead is narrow, hands and feet small, height short,
skin light in color and they are unable to have children.
About 70% of cases occur when part of the father's chromosome 15 is deleted. In another
25% of cases the person has two copies of chromosome 15 from their mother and none
from their father. As parts of the chromosome from the mother are turned off they end up
with no working copies of certain genes.
PWS is not generally inherited but instead the genetic changes happen during the
formation of the egg, sperm, or in early development. There are no known risk factors.

Williams Beuren syndrome

(variants affecting directly multiple genes)

Deletion of a region: the region that is deleted contains a lot of genes,

among which the gene encoding for elastin (congenital vascular and heart

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diseases). Little is known about the implications of the other genes, but we can understand what they code for by
analyzing the symptoms and the phenotypic features of the people affected by this disease.

One of these genes for example is involved in the expression of a chromatin-remodeling protein.

Cognitive features:
Physical and clinical characteristics:  IQ 40-80;
 Facial dysmorphisms;  Visuospatial deficit;
 Connective tissue anomalies;  Language strength.
 Congenital vascular and heart disease (SVAS);
 Hypertension; Behavioral features:
 Coordination deficit;  Loquacious, sociable, friendly
 Hyperacusis;  Attention deficit;
 Infantile hypercalcaemia;  Hyperactivity, anxiety.
 Impaired glucose tolerance;
 Sensorineural hearing loss. Genetic features:
 5-6% of all cases of ID of genetic origin;
 Incidence: 1/7’500-10’000;
 Sporadic inheritance.

Laboratory methods for WBS diagnosis:

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Charghe syndorme
(variants affecting indirectly multiple genes)

Complex development disorder due to haploinsufficiency:

heterozygous loss of function mutations in CHD7 (chromodomain
helicase DNA -binding protein 7).

Gene encoding for helicase: one gene is affected directly by the

disease, but consequently many others are affected.

CHARGE stands for Coloboma - Heart anomaly - Atresia (choanal) -

Retardation - Genital - Ear anomalies.

Incidence: 1/12’000.

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WIKIPEDIA: CHARGE SYNDROME

CHARGE syndrome (formerly known as CHARGE association), is a rare syndrome caused by a genetic disorder. First
described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of
coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital
and/or urinary abnormalities and ear abnormalities and deafness. These features are no longer used in making a
diagnosis of CHARGE syndrome, but the name remains. About two third of cases are due to a CHD7 mutation.
CHARGE syndrome was formerly referred to as CHARGE association, which indicates a non-random pattern of
congenital anomalies that occurs together more frequently than one would expect on the basis of chance. Very few
people with CHARGE will have 100% of its known features. In 2004, mutations on the CHD7 gene (located on
Chromosome 8) were found in 10 of 17 patients in the Netherlands, making CHARGE an official syndrome. A US study
of 110 individuals with CHARGE syndrome showed that 60% of those tested had a mutation of the CHD7 gene.
In 2010, a review of 379 clinically diagnosed cases of CHARGE syndrome, in which CHD7 mutation testing was
undertaken found that 67% of cases were due to a CHD7 mutation.[7] CHD7 is a member of the chromodomain
helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling.
Smith-Magenis syndrome
Recurrent deletion including more genes; however, just one is implicated in the phenotype.
Only 50% of patients that are suspected to have this disease have an actual molecular
diagnosis; among these 90% exhibit a complete deletion and only 10% a loss of function.

WIKIPEDIA: SMITH-MAGENIS SYNDROME

Smith–Magenis Syndrome (SMS) is a developmental disorder affecting the body and brain. Features include
intellectual disability, facial features such as a broad face, difficulty sleeping, and numerous behavioral problems.
Smith–Magenis syndrome affects an estimated 1 in 25,000 individuals. It is a microdeletion syndrome characterized
by an abnormality in the short (p) arm of chromosome 17 and is sometimes called the 17p- syndrome.

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Facial features of children with Smith-Magenis syndrome include a broad face, deep-set eyes, large cheeks and a
prominent jaw, as well as a flat nose bridge. The mouth curves downwards and the upper lip curves outwards. These
facial features become more noticeable as the individual ages.
Disrupted sleep patterns are characteristic of Smith–Magenis syndrome, typically beginning early in life. Affected
people may be very sleepy during the day, but have trouble falling asleep and awaken several times each night, due
to an inverted circadian rhythm of melatonin.
People with Smith–Magenis syndrome have engaging personalities, but all also have a lot behavioral problems.
These behavioral problems include frequent temper tantrums and outbursts, aggression, anger, fidgeting, compulsive
behavior, anxiety, impulsiveness and difficulty paying attention. Self-injury, including biting, hitting, head banging
and skin picking, is very common. Repetitive self-hugging is a behavioral trait that may be unique to Smith–Magenis
syndrome. People with this condition may also compulsively lick their fingers and flip pages of books and magazines
(a behavior known as "lick and flip"), as well as possessing an impressive ability to recall a wide range of small details
about people or subject-specific trivia.
Other symptoms can include short stature, abnormal curvature of the spine (scoliosis), reduced sensitivity to pain and
temperature, and a hoarse voice. Some people with this disorder have ear abnormalities that lead to hearing loss.
Affected individuals may have eye abnormalities that cause nearsightedness (myopia), strabismus and other
problems with vision. Heart and kidney defects also have been reported in people with Smith–Magenis syndrome.

Smith–Magenis syndrome is a chromosomal condition related to low copy repeats of specific segments of
chromosome 17. Most people with SMS have a deletion of genetic material from a specific region of chromosome 17
(17p11.2). Although this region contains multiple genes, recently researchers discovered that the loss of one
particular gene the retinoic acid induced 1 or RAI1 is responsible for most of the characteristic features of this
condition. Also, other genes within the chromosome 17 contribute to the variability and severity of the clinical
features. The loss of other genes in the deleted region may help explain why the features of Smith–Magenis
syndrome vary among affected individuals. A small percentage of people with Smith–Magenis syndrome have a
mutation in the RAI1 gene instead of a chromosomal deletion.
These deletions and mutations lead to the production of an abnormal or nonfunctional version of the RAI1 protein.
RAI1 is a transcription factor that regulates the expression of multiple genes, including several that are involved in
controlling circadian rhythm, such as CLOCK.
SMS is typically not inherited. This condition usually results from a genetic change that occurs during the formation of
reproductive cells (eggs or sperm) or in early fetal development. People with Smith–Magenis syndrome most often
have no history of the condition in their family.

GAIN OF FUNCTION: examples

Overexpression: can be neutral (not giving any bad effect), pathogenic or even advantageous.

1. NEUTRAL: no obvious differences to phenotype and the expression can be comparable with that of the
normal condition; most of the genes in chromosome 21 in individuals with trisomy of chromosome 21 are
overexpressed but have no negative effect on the individual.

2. ADVANTAGEOUS: more copies of one gene in the same chromosome, in the same allele (one allele presents
three copies, the other six copies etc.). Multiple copies can be an advantage in an evolutionary point of view:
for example α-amylase. However, it is a recent phenomenon (occurred after humans became different from
chimpanzee).

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3. Sometimes, it can be PATHOGENIC: the genes that encode for products that have a negative effect if
overexpressed are DOSAGE-SENSITIVE GENES.

Charcot-Marie-Tooth 1A disease
Hereditary disease of the motor neurons. Enzymes that catalyze production of cholesterol are impaired. Myelination
is therefore impaired, causing slow conductance of neurons.We also have the upregulation of cholinergic receptors
that increase Ca++ level in Schwann cells, causing segmental demyelination.

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ACHONDROPLASIA

 Achondroplasia is a common cause of dwarfism.  cioè, il nanismo (=essere bassi) può essere
cuasato da varie gentic disease, la più frequente è achondroplasia
 People with achondroplasia have short stature. In prticluar, the arms and legs are less developed than
the trunk.
 CAUSE: Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). In
normal development FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the
mutated form of the receptor is constitutively active and this leads to severely shortened bones.
The effect is genetically dominant, with one mutant copy of the FGFR3 gene being sufficient to cause
achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or
shortly after birth (known as a lethal allele). A person with achondroplasia thus has a 50% chance of
passing dwarfism to each of their offspring.
 Most of infants with FGFR3 mutations are born to parents without FGFR3 mutations, and there is a
strong correlation with advanced paternal age, particularly over 35 years. These findings were initially
attributed to increased mutability of FGFR3 during spermatogenesis. However, recent observations have
led to the alternative explanation, that sperm bearing mutant FGFR3 have a selective advantage over
sperm bearing normal FGFR3, which could explain how a pool of premeiotic cells harbouring an FGFR3
mutation could increase in relative size with age and lead to the observed correlation with older paternal
age.
 The binding of ligands, fibroblast growth factor (FGF), to FGFR3 monomers leads to receptor’s
dimerization and phosphorylation of adaptors protein. The mutated receptor is consituvely active
because the mutation maked the dimer more stable. FGFR3 signals , propagated through STAT1,
MAPK-ERK, MAPK-p38, and other pathways, causa
o inhibit chondrocyte proliferation,
o post-mitotic matrix synthesis,
o terminal (hypertrophic) differentiation.
 FGFR3 is one of many physiological regulators of linear bone growth. It normally functions as an
inhibitor, acting negatively on both proliferation and terminal differentiation of growth plate chondrocytes,
the region in a long bone between the epiphysis and diaphysis where growth in length occurs.
Achondroplasia mutations are thought to exaggerate this normal physiological function.
 Following activation, FGFR3 is internalized within endosomes and is subject to at least three fates: may
be either recycled to the surface as activated receptors or targeted to lysosomes or proteasomes for
degradation
 The only current treatment consists of Leg lengthening through breaking the bone and then pull the
estremities till when healing is achieved by the formation of bone callus
 Possible treatment could be FGFR3 inibithors or antagonist
 In caso in cui un bimbo sia affetto da achondroplasia e I suoi genitori no, qual è il rischi di recurrence se
hanno un altro figlio ? the recurrence risk for additional children of his parents is small (less than 1 %),
owing to the possibility of either parent having germline mosaicism for the mutation.

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Achondroplasia
Part of a spectrum of disorders, all involved in gain-of-function
mutations.
More than 95% of these mutations are point mutations with a very
precise spot.

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The binding of ligands
(fibroblasts growth factors)
lead to dimerization of a
receptor whose role is to limit
growth. Tyrosine-kinase
activity promoting
phosphorylation of tyrosine.
Normally the FGFR3 pathway
inhibits the growth of
chondrocytes.
However, in this pathologic
condition, the mutation
upregulates this receptors,
which becomes hyperactive,
so the inhibition is
exaggerated.

FGFR3 activates at least three pathways in the nucleus, promoting matrix synthesis, terminal differentiation and
mitosis in the nucleus.

The mutation takes place at

transmembrane level and
renders the receptor
stronger, so that is does not
dimerize in response to
growth factors. Moreover,
ubiquitination is disrupted.
So this receptor is even more
active.
WIKIPEDIA:
ACHONDROPLASIA
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Achondroplasia is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 80% of cases
(associated with advanced paternal age) or it may be inherited as an autosomal dominant genetic disorder.

People with achondroplasia have short stature (120-130 cm on average). If both parents of a child have
achondroplasia, and both parents pass on the mutant gene, then it is very unlikely that the homozygous child will live
past a few months of its life. The prevalence is approximately 1 in 25,000.

Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). In normal development
FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is
constitutively active and this leads to severely shortened bones. The effect is genetically dominant, with one mutant
copy of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably
fatal (recessive lethal) before or shortly after birth (known as a lethal allele). A person with achondroplasia thus has a
50% chance of passing dwarfism to each of their offspring. People with achondroplasia can be born to parents that
do not have the condition due to spontaneous mutation.

New gene mutations leading to achondroplasia are associated with a father older than the age of 35. Studies have
demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during
spermatogenesis; it is theorized that oogenesis has some regulatory mechanism that prevents the mutation
occurring in females.

NCBI: Alpha-1-antitrypsin-Pittsburgh. A
potent inhibitor of human plasma factor XIa,
kallikrein, and factor XIIf.

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Alpha-1-antitrypsin-Pittsburgh is a human variant that resulted from a point mutation in the plasma protease
inhibitor, alpha 1-antitrypsin (358 Met----Arg). This defect in the alpha 1-antitrypsin molecule causes it to have
greatly diminished anti-elastase activity but markedly increased antithrombin activity. In this report, we demonstrate
that this variant protein also has greatly increased inhibitory activity towards the arginine-specific enzymes of the
contact system of plasma proteolysis (Factor XIa, kallikrein, and Factor XIIf), in contrast to normal alpha 1-
antitrypsin, which has modest to no inhibitory activity towards these enzymes. We determined the second-order-
inactivation rate constant (k'') of purified, human Factor XIa by purified alpha 1-antitrypsin-Pittsburgh and found it to
be 5.1 X 10(5) M-1 s-1 (23 degrees C), which is a 7,700-fold increase over the k'' for Factor XIa by its major inhibitor,
normal purified alpha 1-antitrypsin (i.e., 6.6 X 10(1) M-1 s-1). Human plasma kallikrein, which is poorly inhibited by
alpha 1-antitrypsin (k'' = 4.2 M-1 s-1), exhibited a k'' for alpha 1-antitrypsin-Pittsburgh of 8.9 X 10(4) M-1 s-1 (a
21,000-fold increase), making it a more efficient inhibitor than either of the naturally occurring major inhibitors of
kallikrein (C-1-inhibitor and alpha 2-macroglobulin). Factor XIIf, which is not inhibited by normal alpha 1-antitrypsin,
displayed a k'' for alpha 1-antitrypsin-Pittsburgh of 2.5 X 10(4) M-1 s-1. This enhanced inhibitory activity is similar to
the effect of alpha 1-antitrypsin-Pittsburgh that has been reported for thrombin. In addition to its potential as an
anticoagulant, this recently cloned protein may prove to be clinically valuable in the management of septic shock,
hereditary angioedema, or other syndromes involving activation of the surface-mediated plasma proteolytic system.

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