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1.
PCD is an autosomal recessive genetic disorder caused by missense, nonsense, splice site,
insertion, and deletion mutations where at least two different genes have been implicated
thus far:
a.
DNAH5
gene
on
chromosome 5p15-p14
for
ciliary d ynein axonemal heavy chain 5
. This
mutation occurs in 28% of the cases.
b. DNAI1 gene
on
chromosome 9p21-p13
for
dynein axonemal intermediate chain 1
. This
mutation occurs in 10% of the cases.
c.
60% of PCD affected individuals do not have mutations in the DNAH5 gene or DNAI1
gene. It is speculated that mutations in other genes on chromosomes 15q24-25,
15q13.1-q15.1, 16p12.1-p12.2, and 19q13.42-q13.43 for dynein light chains, spoke head
proteins, and other axonemal proteins may be causative.
2.
These mutations result in defective outer dynein arms that results in cilia that are
immotile (ciliary immotility), beat abnormally (ciliary dyskinesia), or are absent (ciliary
aplasia).
3.
PCD affected individuals inherit the mutant genes from the parents who are obligate
asymptomatic heterozygotes.
4. Prevalence.
The prevalence of PCD is 1/12,000 to 17,000 births in the US population.
5. Clinical features include
: chronic cough; chronic rhinitis; chronic sinusitis; chronic/
recurrent ear infections; recurrent sinus/pulmonary infections due to a defect of cilia
in the respiratory pathways; neonatal respiratory distress; digital clubbing; sterility in
males (retarded sperm movement); situs inversus totalis (mirror-image reversal of all
visceral organs with no apparent consequences; PCD with situs inversus totalis is
called
Kartagener syndrome
); heterotaxy (discordance of right and left patterns of
ordinarily asymmetrical structures with significant malformations; for example asple-
nia or polysplenia); the gold standard diagnostic test is the appearance of ciliary
ultrastructural defects obtained by electron microscopy of a respiratory epithelium
biopsy.
Chapter 15
Genetics of Development
155
V. DETERMINATION OF THE ANTERIOR/POSTERIOR (A/P) AXIS
A/P axis determination is established by the formation of the
primitive streak,
which involves
the expression of the signaling protein
nodal protein
(a member of the TGF-
family).
A.
A large number of gene regulatory proteins called
homeodomain proteins
play a role in deter-
mining the normal A/P location of a number of anatomical structures.
B.
All homeotic genes encode for homeodomain proteins, which are gene regulatory pro-
teins. Homeotic genes contain a 180 base pair sequence (called a
homeobox
) that
encodes a 60 amino acid long region (called a
homeodomain
) that binds specifically to
DNA segments.
C.
A
homeotic mutation
is one in which one body part is substituted for another. Homeotic
mutations were first studied in Drosophila (e.g., legs sprout from the head in place of anten-
nae). The genes involved in homeotic mutations are called
homeotic genes
, which are collec-
tively referred to as the
HOM-complex.
D. Clustered Human Homeotic Genes.
There are 39 clustered homeotic genes identified in
humans thus far. They are organized into four gene clusters (
HoxA, HoxB, HoxC, and HoxD
)
collectively called the
Hox-complex
. In addition, there are numerous
nonclustered homeotic
genes
randomly dispersed throughout the human genome.
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VI. GROWTH AND DIFFERENTIATION (Figure 15-1)
The close range interaction between two or more cells or tissues of different histories is
called
induction
. Induction involves an
inducer
(a cell or tissue that produces a signal that
changes the behavior of another cell or tissue) and a
responder
(a cell or tissue that is
induced). The inducer and responder may interact by either
juxtacrine interactions
or
paracrine interactions
. Juxtacrine interactions occur when cell membrane receptors on the
inducer interact with cell membrane receptors on the responder. Paracrine interactions
occur when the inducer secretes a protein that diffuses across a small distance and binds
to a cell membrane receptor on the responder. These diffusible proteins are called
paracrine factors
or
growth and differentiation factors (GDFs).
When a paracrine factor binds
to a cell membrane receptor on the responder a series of reactions occurs called a
signal
transduction pathway
. The end point of a signal transduction pathway is either
activation or
deactivation of transcription factors
(i.e., the responder expresses different genes) or the
reg-
ulation of the cytoskeleton
(responder changes shape or is permitted to migrate). An impor-
tant family of paracrine factors is the fibroblast growth factor (FGF) family as indicated
below.
A. Fibroblast Growth Factor (FGF) Family.
The FGF family has nine members
(FGF1-FGF9)
along
with a number of isoforms
.
FGFs bind to
FGF receptors (FGFRs).
The FGFR family has four
members
(FGFR1-FGFR4).
FGFRs are highly homologous glycoproteins with a signal peptide
domain, three immunoglobulinlike domains (IgI-IgIII), an acid box domain, a transmem-
brane domain, and two intracellular tyrosine kinase domains (i.e.,
receptor tyrosine kinases
).
FGFRs subsequently act through two major signal transduction pathways called the
receptor
tyrosine kinase pathway (RTK pathway)
and the
Janus kinase –signal transducers and activators
of t ranscription pathway (JAK/STAT pathway).
B. Clinical Considerations.
1. Achondroplasia (AC). Skeletal dysplasias
are conditions of abnormal bone growth and are
typically called
dwarfisms
. There are
short-limb dysplasias
(short limbs relative to the
length of the trunk) and
short-trunk dysplasias
(short trunk relative to the length of the
limbs). AC is a short-limb dysplasia.
a.
AC is an autosomal dominant genetic disorder caused by a missense mutation in the
FGFR3 gene
on
chromosome 4p16.3
for the
f ibroblast growth factor receptor 3
.
b.
The most common mutation is a G
→
A transition at
nucleotide position 1138 (G1138A)
which results in a
normal glycine
→
arginine
substitution at position 380 (G380R) in the
transmembrane domain
of FGFR3.
c.
This mutation results in
constitutive activation
of FGFR3 (i.e., a
gain-of-function muta-
tion
) which indicates that FGFR3 normally inhibits bone growth.
d.
Most AC affected individuals have a de novo mutation. The de novo mutation usually
occurs during spermatogenesis in the unaffected advanced-aged father. Chances of AC
increase with increasing paternal age.
e. Prevalence.
The prevalence of AC is 1/26,000 to 40,000 births. This is the most common
type of dwarfism.
f. Clinical features include:
short stature, proximal shortening of arms and legs with
redundant skin folds, limitation of elbow extension, trident configuration of hands,
bow legs, thoracolumbar gibbus in infancy, exaggerated lumbar lordosis, large head
with frontal bossing, and midface hypoplasia; mental function is not affected.
2. Hypochondroplasia (HP).
HP is a short-limb dysplasia.
a.
HP is an autosomal dominant genetic disorder caused by a missense mutation in the
FGFR3 gene
on
chromosome 4p16.3
for the
f ibroblast growth factor receptor 3.
b.
One of the most common mutations is a C
→
A transition at
nucleotide position 1620
(C1620A)
which results in a
normal asparagine
→
lysine
substitution at position 540
(N540K) in the first
tyrosine kinase domain
of FGFR3.
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c.
This mutation results in
constitutive activation
of FGFR3 (i.e., a
gain-of-function muta-
tion
) which indicates that FGFR3 normally inhibits bone growth.
d.
Most HP affected individuals have a de novo mutation. The de novo mutation usually
occurs during spermatogenesis in the unaffected advanced-age father. Chances of HP
increase with increasing paternal age.
e. Prevalence.
The prevalence of HP is 1/15,000 to 40,000 births.
f. Clinical features include:
short stature, stocky build, disproportionately short arms
and legs, broad, short hands and feet, mild joint laxity, and macrocephaly.
The
skeletal features are very similar to AC but generally more mild with less craniofacial
involvement.
3. Thanatophoric dysplasia (TD).
TD is a short-limb dysplasia and is the
most common of the
“lethal skeletal dysplasias.”
There are two types of TD.
a.
Type 1 TD is an autosomal dominant genetic disorder caused by a missense mutation
in the
FGFR3 gene
on
chromosome 4p16.3
for the
f ibroblast growth factor receptor 3.
This
results in a
normal arginine
→
cysteine
substitution at position 248 (R248C) in the
region
between IgII-IgIII domains
of FGFR3.
b.
Type 2 TD is an autosomal dominant genetic disorder caused by a mutation in the
FGFR3 gene
on
chromosome 4p16.3
for the
f ibroblast growth factor receptor 3.
This results
in a
normal lysine
→
glutamic acid
substitution at position 650 (K650E) in the second
tyrosine kinase domain
of FGFR3.
c.
These mutations result in
constitutive activation
of FGFR3 (i.e., a
gain-of-function muta-
tion
) which indicates that FGFR3 normally inhibits bone growth.
d.
Most TD affected individuals have a de novo mutation. The de novo mutation usually
occurs during spermatogenesis in the unaffected advanced-age father. Chances of TD
increase with increasing paternal age.
e. Prevalence.
The prevalence of TD is 1/20,000 to 50,000 births.
f. Clinical features include:
short ribs, narrow thorax, macrocephaly, distinctive facial fea-
tures, brachydactyly, hypotonia, and redundant skin folds along the limbs;
children
with TD usually die in the perinatal period
with only a few survivors into early childhood;
a narrow thoracic cage which leads to respiratory compromise; curved long bones; type
1 TD is characterized by micromelia with bowed femurs and generally without a clover-
leaf-shaped skull; type 2 TD is characterized by micromelia with straight long bones
and generally with a cloverleaf-shaped skull.
4. Crouzon syndrome (CR).
CR is one of eight FGFR-related craniosynostosis syndromes,
which include Pfeiffer syndrome, Apert syndrome, Beare-Stevenson syndrome, FGFR2-
related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with
acanthosis nigricans, and Muenke syndrome.
a.
CR is an autosomal dominant genetic disorder caused by a missense mutations in the
FGFR2 gene
on
chromosome 10q25-q26
for
f ibroblast growth factor receptor 2.
b.
These missense mutations include a
normal cysteine
→
tyrosine
substitution at position
342 (C342Y), a
normal cysteine
→
arginine
substitution at position 342 (C342R), a
normal
cysteine
→
tryptophan
substitution at position 342 (C342W), or a
normal cysteine
→
phenylalanine
substitution at position 278 (C278F) in the
IgIII domain
of FGFR2 (the so-
called “cysteine mutational hotspot”).
c.
These missense mutations result in
constitutive activation
of FGFR2 (i.e., a
gain-of-function
mutation
) which indicates that FGFR2 normally inhibits bone growth.
d.
Most CR affected individuals inherit a mutant gene from an affected parent whereas
some CR affected individuals have a de novo mutation. The de novo mutation usually
occurs during spermatogenesis in the unaffected advanced-aged father. Chances of CR
increase with increasing paternal age.
e. Prevalence.
The prevalence of CR is 1/62,500 births. The prevalence for all forms of
FGFR-related craniosynostosis syndromes 1/2,000 to 2,500 births.
f. Clinical features of CR include:
premature craniosynostosis, midface hypoplasia with
shallow orbits, ocular proptosis, mandibular prognathism, normal extremities, pro-
gressive hydrocephalus, and no mental retardation.
Chapter 15
Genetics of Development
157
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158
Board Review Series Genetics
FGF
FGF
P
P
P
P
FGFR
SOS
GNRP
GDP
RAS
GTP
RAS
RAF
MEK
ERK
Transcription
factor
P
FGF
FGF
P
P
P
P
P
P
FGFR
STAT
STAT
Inducer cell
Inducer cell
Responder cell
Responder cell
JAK
JAK
P
STAT
P
STAT
P
STAT
P
DNA
DNA
Transcription
factors
B
C
A
X T
X T
X T
X T
X T
X T
X A
X A
X A
X T
X T
X A
X T
X A
X T
X T
X T
X H
X T
SP
IgI
AB
IgII
IgIII
TM
KINASE
KINASE
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Chapter 15
Genetics of Development
159
FIGURE 15-1. Fibroblast growth factor (FGF) receptor 3 and
signal transduction pathways. (A) Diagram of the FGF recep-
tor 3.
Diagram shows important functional domains, which include a signal peptide (SP), three immunoglobulinlike
domains (Ig), and acid box (AB), a transmembrane domain (TM), and two tyrosine kinase domains (Kinase). The location
of various point mutations (x’s) causing achondroplasia (A), hypochondroplasia (H), and thanatophoric dysplasia (T) are
indicated. (B) RTK (receptor tyrosine kinase) pathway. When FGF (fibroblast growth factor) binds to the FGFR (fibroblast
growth factor receptor), autophosphorylation of FGFR occurs. This is recognized by SOS adaptor protein, which activates
GNRP (guanine nucleotide releasing factor). GNRP (guanine nucleotide releasing factor) activates the G protein RAS by
exchanging a PO
4
2
from GTP to transform the bound GDP to GTP (RAS-GDP
→
RAS-GTP). RAS-GTP activates the kinase
RAF, which activates the kinase MEK, which then activates the kinase ERK. ERK enters the nucleus and phosphorylates
transcription factors, which then modulate gene expression activity. The flow of RTK pathway is: FGF
→
RTK
→
GNRP
→
RAS
→
RAF
→
MEK
→
ERK
→
Transcription factors. (C) JAK (Janus kinase)/ STAT (signal transducers and activators of
transcription) pathway.
When FGF binds to other receptors linked to JAK, the receptors dimerize and the JAK proteins
phosphorylate each other and the dimerized receptors, which activates the dormant kinase activity of the receptor. The
activated receptor phosphorylates STAT, which allows STAT to dimerize. The activated dimerized STAT enters the nucleus
and along with other transcription factors modulates gene expression activity. The flow of the JAK/STAT pathway is:
FGF
→
FGFR
→
JAK
→
STAT
→
STAT dimerization
→
Transcription factors.
VII. FORMATION OF THE EXTRACELLULAR MATRIX (ECM)
The ECM consists of various macromolecules secreted by cells (e.g., mesenchymal cells,
fibroblasts, chondroblasts, osteoblasts) and forms a noncellular material in the interstices
between cells. The ECM is not inert but instead plays an important embryological role in cell
adhesion, cell migration, and formation of epithelial sheets. The ECM consists of proteogly-
cans, glycoproteins, and fibers (i.e., collagen and elastic fibers).
A. Proteoglycans.
Proteoglycans bind paracrine factors (e.g., FGF, Shh, Wnt, and TGF-
super-
family) secreted by an inducer cell and deliver the paracrine factors in high concentration to
their respective receptors located on the responder cell. Specific proteoglycans include the
following:
aggrecan, betaglycan, decorin, perlecan
, and
syndecan-1
.
B. Glycoproteins.
Glycoproteins play a role in cell migration and modulation of gene expression
activity. Specific glycoproteins include the following:
fibronectin, laminin, chondronectin,
osteocalcin, osteopontin,
and
bone sialoprotein
.
C. Collagen and Elastic Fibers.
Collagen is a family of proteins consisting of three polypeptide
-chains
that form a triple-stranded helical structure. There are 25 distinct collagen
-chain
genes. However, only
20 different types of collagens (types I-XX) have been isolated.
Elastic
fibers
consist of an amorphous core of the
elastin
protein surrounded by microfibrils of the
fibrillin
protein.
1. Osteogenesis imperfecta (OI).
OI is a group of disorders (types I-VII) with a continuum
ranging from perinatal lethality
→
severe skeletal deformities
→
nearly asymptomatic
individuals.
a.
OI (types I-IV) are autosomal dominant genetic disorders caused by mutations where
at least two different genes have been implicated thus far:
i. COL1A1 gene
on
chromosome 17q21.3-q22
for
collagen pro
-1 (I ) chain of Type I pro-
collagen
ii. COL1A2 gene
on
chromosome 7q22.1
for
collagen pro
-2 (I ) chain of Type I procollagen.
b.
Type I OI is most commonly caused by a
frameshift mutation
or a
RNA splicing mutation
(that forms a premature STOP codon, shifts a reading frame, or produces unstable
mRNAs).
c.
Types II, III, and IV OI are most commonly caused by a
missense mutation
which results
in a normal glycine
→
serine, normal glycine
→
arginine, normal glycine
→
cysteine, or
normal glycine
→
tryptophan substitution which alters the structure of the
1(I)-chain
or the
2(I)-chain since glycine is necessary for normal folding of the collagen helix.
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