Mother: The ONLY Visible GOD I Know.

GOD Cant Come in Person to Help You. He Will Send Some One in the
Form of Homosepian, Believe it. The Only Thing What You Are Going to
Take Away is Karma _Educate_Dr P Kumar, BIO-GEN.

COGNITIVE CONCEPT MAP ON XERODERMA PIGMENTOSUM (XP)

Problem Based Learning (PBL) for Large Groups Medical Students: e-Problem Solving Test: A Mutation Causing Retinoblastoma (Rb)
*International Medical University (IMU),
ST Matthews School of Medicine (SMU),
AIMST-U, MSU, Vinayaka Missions Med School

Dr Kumar Ponnusamy and Dr Jegathambigai Rameshwar Naidu

*
International Medical School (IMS), Management & Science University (MSU), Malaysia
*

Acknowledgements: The Authors Gratefully Acknowlwdges All On-Line Resources Including Google.com, PubMed, Elsieviers Ltd, Eye Cancer Network, Scriibd.com., ect.,.

Xeroderma Pigmentosum (XP): First discovered in late 1800s by Moritz Kaposi Severe lesions, tumors and skin deformations result from sun exposure. Autosomal recessive (AR)
hereditary disease, Incidence: 1 in 250,000 in Western world 1 in 40,000 in Japan, Disease caused by ineffective DNA repair. Median age to develop skin cancer is age 8, Incidence of skin
cancer is elevated 1000 fold under the age of 20. In 1960s, proved XP was due to defective NER. Phenotype can be caused by a mutation in a number of different genes. UV damage to
DNA: UV light causes nucleotide bases to form Thymine-Thymine dimers, disrupt DNA synthesis and lead to mutations. Nucleotide Excision Repair (NER): Responsible for repairing
everyday damage to genome. Scary fact: base damage estimated to occur in 25,000 bases per human cell genome per day ~ thats a lot of error to catch and correct!. A repair
mechanism that works by removing the altered base and allowing for resequencing, Discovery of pathway. Introduction Genomic DNA is highly susceptible to damage caused by its
intrinsic instability, endogenously produced reactive oxygen species and a wide variety of environmental agents such as radiations and chemicals. Some lesions, like double strand
breaks, can directly lead to chromosome aberrations (e.g. deletion, translocation, etc.), whereas structural changes in the bases often interfere with DNA replication in S-phase. When
replicating DNA polymerases are blocked by base lesions on the template strand, the replication forks may collapse, thereby resulting in double strand breaks. In addition, depending
on the type of lesions, certain DNA polymerases are capable of elongating DNA strands across damaged sites, and this translesion DNA synthesis (TLS) is frequently associated with
replication errors, giving rise to mutations. To cope with such deleterious effects of DNA damage promoting carcinogenesis, organisms are equipped with multiple DNA repair systems
(1,2).. Nucleotide excision repair (NER) is a versatile DNA repair system that eliminates a broad spectrum of base lesions generated on one strand, including ultraviolet light (UV)induced cyclobutane pyrimidine dimer (CPD) and pyrimidine (6-4) pyrimidone photoproduct (6-4PP), as well as other bulky base adducts that can be induced by numerous chemical
compounds (1,3). Although these lesions do not share common chemical structures, they are supposed to induce more or less distortion of the DNA helical structure (4). It is known that
defects in NER are associated with several human autosomal recessive hereditary disorders, such as Xeroderma pigmentosum (XP). Patients suffering from XP exhibit extreme
sensitivity to sun exposure and a marked predisposition to skin cancer. Classical complementation analyses using cell fusion have identified eight genetic complementation groups in XP,
for which the genes responsible are already cloned (5) (Table I). Seven of these groups, XP-A through XP-G, are associated with defective NER, while the remaining group, a variant
form of XP (XP-V), is proficient in NER but deficient in a specialized DNA polymerase g (pol g) involved in TLS. This article overviews how these XP gene products function in DNA
repair and prevent carcinogenesis.
The Self-Directed PBL Process Overall (Day-1-Induction; Day -2 Presentation)
DAY 1: Induction of PBL on Xeroderma Pigmentosum (XP)
1 Day 1-Step 1-Trigger 1: Release of the Digital Copy of Picture 1 Shows
the Presentations of Xeroderma Pigmentosum..
2 Day 1-Step 2: Fig 2-Trigger 2: Display of Digital Copy of Karyotype of XP.
3 Day 1- Step 3:Trigger 3: Display of Pedigree Chart on Rb. Figure 3: Genetic
Features of XP.
4 Day 1-Step 4: Research Component on XP-Review Article: URL:
http://www.ojrd.com/content/pdf/1750-1172-6-70.pdf
5 Day 1- Step 5: Matching and Fine Tuning of the Learning Outcomes Arrived by
the Team, Facilitated by Team Leader (Chair-Person of PBL Process).
Day 2: Presentation on Xeroderma Pigmentosum
1 Day 2-Step 1: Presentations and Summarization on XP.
2 Day 2-Step 2: Display of Video Clip on XP.
URL: https://www.youtube.com/watch?v=nDtZyUc1gB8
3 Day 2-Step 3: Construction of cognitive concept mapping. Model Map
on XP: URL: Dr Kumar Ponnusamy, Scribd
4 Day 2-Step 4: Spot Test on Matching Questions on XP.

In persons with XP who carry specific

mutations in the XPD gene. XPD gene
encodes a subunit of the TFII H
required for transcription initiation.
Mutations in XPD could lead to defect In
both DNA repair and transcription.

The PBL Process: Day 1-Step 1-Trigger 1: Release of the Digital Copy of
Fig.1 Shows the Presentations of Xeroderma Pigmentosum Pheno Type

Location of XP Gene Cytogenetics:

3
Molecular Biology
NER: XPC, XPA recognize base damage (mechanism not
understood). Triggers binding of several more proteins, including
XPG. Binding of ERCC1-XPF endonuclease; NER complex
complete. Cleavage and removal of damaged oligonucleotide
fragment. DNA polymerase resynthesizes missing sequence and
ligase reseals backbone. Figure from Friedberg paper

Recessive Inheritance: a phenotype expressed

only in homozygotes (for X-linked, male
hemizygotes) and not in heterozygotes. Most
recessive disorders are due to mutations that reduce
or eliminate function of a gene (i.e., loss-offunction mutations).

GENETICS

Day 1-Step 2:Trigger-2:Fig.2: Display of Digital Copy of XP.

What is the name of the DNA repair system in E. coli in which dual incisions are made
in the damaged part of the double helix, and a 12-13 base segment is removed and
replaced with new DNA?
A. Mismatch repair
B.Base excision repair
C.Nucleotide excision repair
D.AP site repair Answer .C. Nucleotide excision repair (NER) Explanation: Nucleotide

Day 1-Step 3:Trigger 3: Display of DNA Excision Repair Mechanism

excision repair is an almost universal repair mechanism in which a section of damaged DNA is
removed and replaced with new DNA by a DNA polymerase. It is used to repair photoproducts
caused by UV damage and bulky DNA lesions caused by a variety of mutagens.
Dignosis: Initially the diagnosis is predominantly clinical: a young child may be brought to the paediatric department with
bright, confluent erythema over all sun-exposed sites, or with lentigines at an unusually early age in sun-exposed areas. In the
former case, the clinician assessing the child may suspect a skin allergy, drug reaction or even in some cases sunburn caused by
parental neglect. After all differentials are excluded, the clinician would then request cellular tests to assess for defective DNA
repair. This requires a 4 mm punch biopsy of the skin taken from an unexposed site (e.g. buttock area). This specimen is used to
culture fibroblasts followed by UVR exposure and subsequent measurement of unscheduled DNA synthesis (UDS). UDS refers
to the newly synthesised DNA, which is formed when the damaged DNA is excised. UDS can be measured as incorporation of
nucleotides into DNA of the irradiated cells by autoradiography,64 liquid scintillation counting, or fluorescence assay. Typically
a reduced level of UDS confirms diagnosis of XP. Mutational analysis to assign complementation group and define pathogenic
mutation(s) in the affected gene(s) is then performed. Using next-generation sequencing techniques, a platform of DNA repair
genes can be used for rapid identification of both complementation group and mutation analysis. Diagnosis of XP-V is different
as XP-V cells have normal levels of UDS. However, UVR-exposed XP-V cells show an exquisite sensitivity to caffeine, which
impairs their survival. Therefore, if XP-V is suspected, cultured fibroblasts are incubated in caffeine for a few days and their
viability compared to that of normal cells. If UDS is normal and post-UV sensitivity to caffeine is detected, a diagnosis of XP-V
is confirmed. Of the eight genes implicated in XP, mutations in the XP-C gene count for a substantial proportion in most but not
all populations. Immunohistochemistry staining with an antibody for XP-C protein has recently been shown to be a new rapid
and cost-effective method for both diagnosis and potentially as a screening tool in suspected XP-C patients. UVR-protected,
tumour-free skin of XP-C patients will show negative expression of the XP-C protein compared to normal controls. In
principle, use of antibodies to other XP proteins can be used to also look at deficiencies in other XP complementation groups.
However, although this procedure is a rapid method of identifying reductions or absence of protein, as is the case for most XP-C
and XP-V patients, immunohistochemistry cannot be used as a diagnostic tool in many other complementation groups because
pathogenic missense mutations result in production of a defective XP protein present in normal quantity. All the diagnostic
procedures require specialised laboratories and technical skills and are therefore often not available in poorer countries, in
which there may be high incidences of XP.

Treatments & Studies:

Prevention.
Gene therapy.
Dimericine (T4N5 Liposome
Lotion).

Genetic Counseling & Prenatal Diagnsis: As XP is an autosomal recessive disorder with 100% penetrance, it is
only possible to offer prenatal diagnostic testing for XP in a family where parents already have an affected child.72
Counselling and psychological support is of paramount importance in families at reproductive risk. These families can
have prenatal diagnosis by mutational analysis or DNA repair testing on chorionic villus sampling at 10-12 weeks
gestation.73-76 In principle pre-implantation genetic diagnosis can also be carried out, if the pathogenic mutations are
known and the carrier status of both parents confirmed, although to our knowledge this has not yet been done for XP.

Q. Which of the following autosomal recessive disorder is associated with development of skin
malignancies?
Note & Disclaimer: The content in this e-Cognitive Concept Map on BIO-GEN is based on the knowledge that
I acquired studying regular reference books and On-Line Learning Resources in Google, PUBMed ect., and
A.Peutz Jeghers
after years of teaching biochemistry-Genetics to Medical and Allied Health Science students in PBL Based
B.Tuberous sclerosis
Integrated Med Curriculum. The sourvce of the figures, animation used in this Map is mentioned where ever
applicable, and they are used purely for teaching Biochemistry-Genetics to audience and no monetary benefit
C.Neurofibromatosis
intended out of it. If copyright owner of the figures used in this Map do not agree with this disclaimer, they are
D.Xeroderma pigmentosa
welcome to contact me about it and, I will delete their content and source from my presentation. Thanking You!.
E.Familial polyposis coli
Answer D: Xeroderma pigmentosa is an autosomal recessive (AR) condition in which the ability of DNA
to repair damaged caused by UV light is deficient 2. Even the slightest amount of sunlight can induce
skin cancer in this disorder 3. Multiple basal cell cancers and melanomas usually appear at a young age.
The disorder is most common in Japanese individuals 4. The defects is because of the defective
nucleotide excision repair enzymes.
Xeroderma pigmentosum is produced as a result of a defect in :
A. DNA polymerase III
B. DNA polymerase I
C. DNA exonuclease
D. DNA ligase
Answer:B. DNA polymerase I or D. DNA ligase.
Xeroderma pigmentosum is an autosomal recessive disease with defect in DNA repair. It is characterised
by extreme sensitivity to sunlight. The enzymes affected in this condition are:
1. UV specific endonuclease (most common)
2. DNA polymerase I
3. DNA ligase.

Research
Component
on XP

Which of the following is the name of the human

genetic disorder resulting from defects in nucleotide
excision repair?
A.Hereditary nonpolyposis colorectal cancer (HNPCC)
B.Xeroderma pigmentosum (XP)
C.Lynch syndrome
D.Diabetes
Answer B. Xeroderma pigmentosum (XP)
.Explanation.: People born with the disorder, xeroderma
pigmentosum, have a mutation in one of the genes coding
for nucleotide excision repair enzymes. Therefore they are
unable to carry out efficient repair on sunlight damage and
they are hypersensitive to sunlight. They have to protect
their skin from daylight or risk getting skin cancer.

5
What is XPF?: In the NER pathway, XPF forms a
heterodimeric endonuclease with ERCC1.
The ERCC1-XPF protein is responsible for splicing
the 5 end of the damaged sequence.

6
7

ETHICS: GENETIC COUNSELING & REFERRAL TO

SPECILITY CLINICS ON XP & SUPPORT GROUPS.

References: [1] . Lee J. Martin, DNA Damage and Repair: Relevance to Mechanisms of Neurodegeneration. J Neuropathol Exp
Neurol. 2008 May ; 67(5): 377387.