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1027660

MOD003080

Polydactyly
Introduction
Polydactyly (PPD) is one of the most frequently observed congenital hand malformations with
a prevalence of 2 per 1000 live births (Sun, et al
...
There is a surplus of classification
types with various manifestations
...
Mutations causing polydactyly have also been associated with other
disorders such as Werner’s mesomelic syndrome and dwarfism
...
e x-ray and surgical
procedures respectively
...

Complementary expression of transcription factors Gli3 in the anterior half and HAND2 in the
posterior half of the limb bud are first molecular indications of limb polarity, this predisposes
the posterior region of the limb bud to express the SHH gene (Figure 1)
...

SHH signal regulates proteolytic processing of Gli proteins, specifically Gli3
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This relative concentration of Gli3A:Gli3R
across the developing limb bud specifies the differences between fingers
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Figure 1
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A) Polarization via anteriori Gli3 expression and posterioir HAND2
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C) Distal Production of ETS1/GABPα in overlapping
paterns
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Limb bud development in relation to ZPA (Carlson
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In the receiving cell in the absence of hedgehog ligand
(off-state) the patched receptor is associated with smoothened (Smo), a G-coupled
transmembrane protein, and prevents its membrane incorporation
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, 2010)
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In the on-state HH binding
sequesters the co-receptor Ihog to patched that permits β-arrestin to freely facilitate
incorporation of smoothened to the primary cilium membrane
...

Table 1
...
,
2006)
Protein

Function

Disease involvement

Gli1

Transcriptional activator , mediates Sonic hedgehog
signalling
Transcriptional activator, , mediates Sonic hedgehog
signalling
Dual function as transcriptional activator and repressor of
the sonic hedgehog pathway

Unknown

Gli2
Gli3

Sonic
Hedgehog
Patched
SuFu

Binds to patched receptor, in association with
smoothened, to activate transcription of target genes
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SHH on-state & off-state pathway within primary cilium (Chi, et al
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ZRS is located inside an intron
of the limb region homolog (Lmbr1) gene that has no known role in limb development and
operates over a long distance to activate Shh promoter 800 kb-1 Mb away
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,
2003) similar to the effects of grafted ZPA’s in figure 1C
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Mutations in the ZRS region can give rise to such disorders as
Werners mesomelic syndrome (Wieczorek, et al
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Other point mutations of the ZRS have
shown to give rise to additional ETS1/GABPα causing ectopic expression of SHH at the
anterior margin and thus extra digit formation (Lattice, et al
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Haas type polysndactyly
is another ZRS mutation that involves intrachromosomal duplications leading to tandem
duplication of the ZRS however the molecular mechanisms for this phenotype is unknown
(Carlson
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1027660

MOD003080

Polydactyly can clinical manifest itself in a variety of phenotypes (Table 2)
...
Treatment for polydactyly is relatively
simple ranging from vascular clips which inhibit the circulation of soft tissue digits causing
necrosis of the digit with eventual excision and surgical removal for bone containing digits
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If polydactyly is
identified prenatal by sonography than further genetic analysis is required to examine possible
associated disorders (table 3)
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Phenotypic manifestation of Polydactyly with inheritance with locus and gene
locations
...
1; GLI3

Table 3
...
, 2003), (Roessler, et
al
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Disorder
Holoprosencephaly
Pallister-Hall syndrome
Medulloblastoma
Greig cephalo-poly-syndactyly
Werners mesomelic syndrome

Diagnosis
Karyotyping via array-CGH analysis
Denaturing high-performance liquid
chromatography and PCR
MRI
Denaturing high-performance liquid
chromatography and PCR
Ultrasonography

In conclusion Polydactyly is still a disorder which requires further investigation specifically
within its associated pathways such as SHH in order to fully understand the molecular
mechanisms
...

Although polydactylous patients are able to easily treat the digits via surgical removal, the true
danger lies in the associated disorders that are related which further reflects the difficulty in
prenatal diagnosis shedding light into the need for more specific genetic detection
...
M
...
Human embryology and developmental biology
...

Chi, S
...
, Liu, H
...
, Zhang, X
...
, & Xie, J
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Rab23 negatively regulates Gli1
transcriptional factor in a Su (Fu)-dependent manner
...

Debeer, P
...
, Driess, S
...
, Freese, K
...
, & Kalff‐Suske, M
...

Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4
independent families and 3 sporadic cases with identified GLI3 mutations
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Lettice, L
...
, Heaney, S
...
, Purdie, L
...
, Li, L
...
, Oostra, B
...
, & de Graaff, E
...
A
long-range Shh enhancer regulates expression in the developing limb and fin and is associated with
preaxial polydactyly
...

Lettice, L
...
, Williamson, I
...
H
...
, Devenney, P
...
, Hill, A
...
, & Hill, R
...
(2012)
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Developmental cell, 22(2), 459-467
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, Ribeiro, L
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, de Miranda, E
...
, & Murray, J
...
(2006)
...

Roessler, E
...
B
...
, Vélez, J
...
, Solomon, B
...
, Pineda‐Álvarez, D
...
&
Muenke, M
...
The mutational spectrum of holoprosencephaly‐associated changes within the SHH
gene in humans predicts loss‐of‐function through either key structural alterations of the ligand or its
altered synthesis
...
Ptch:
Chi, S
...
, Liu, H
...
, Zhang, X
...
, & Xie, J
...
Rab23 negatively regulates Gli1
transcriptional factor in a Su (Fu)-dependent manner
...

Sun, G
...
M
...
F
...
, & Tang, D
...
(2011)
...
World journal of pediatrics, 7(4), 331336
...
W
...
T
...
Mechanism and evolution of cytosolic Hedgehog signal
transduction
...

Wieczorek, D
...
, Li, Y
...
A
...
, May, K
...
, & Wollnik, B
...
A specific
mutation in the distant sonic hedgehog (SHH) cis‐regulator (ZRS) causes Werner mesomelic syndrome
(WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly
(PPD) with or without triphalangeal thumb
...


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