DNA REPAIR DEFICIENCY DISEASES

1. DNA REPAIR
DEFICIENCY
DISEASES
Submitted by
SIMNA SIDDIQUE
1st MSC ZOOLOGY
GOVT.WOMENS COLLEGE ,TRIVANDRUM

2. DNA DAMAGES
• DNA is subjected to both endogenous and exogenous mutagenesis
• Endogenous agents- replication stress, effects of O2, freeradicals
• Exogenous agents- UV & ionizing radiations, alkylating agents ,etc.
• Mutations in actively transcribed genes are repaired before dna replication.

3. DNA REPAIR MECHANISMS
• Nucleotide excision repair
• Base excision repair ( Single strand breakage repair)
• Mismatch repair
• Double strand breakage repair
 Unrepaired DNA damages accumulate in non replicating cells like neurons , and
can cause aging( DNA damage theory of aging).
 In replicating cells errors upon replication can give rise to mutations and
epigenetic alterations.

4. Syndromes are classified according to the defects in
• Nucleotide excision repair (NER)
• DNA single-strand break repair (SSBR).
• DNA double-strand break repair (DSBR).

5. Disorders
Repair Pathways
DNA damage
DNA
Bulky
lesions
NER
Xeroderma
Pigmentos
um
Cockyn
e
syndrom
e
TTD
Base
modific
ations
SSBR
Triple A
syndrom
e
Cross
links
DSBR
Ataxia
telandi
ectasia
Fanconi
anemia
Bloom
syndrome
Werner
syndrome
Rothmun
d
Thomson
syndrome
Nigemeg
an
breakag
e
syndrom
e

6. XERODERMA PIGMENTOSUM
• Rare autosomal recessive disorder
• Deficient in the repair of UV induced damage in DNA, such as thymine
dimers,deficiency of nucleotide excision repair
• Defective genes- XPA, XPB, XPD, XPF, XPG, XPV
• High sensitivity to light
• Freckle like pigmentation and lesions in areas exposed to sunlight
• 20 to 30% of XP patients show progressive neurological disease
• High frequency of developing basal and squamous cell carcinomas on sun-exposed areas of the skin
• Even very limited exposure to direct rays of sun produce dark pigmented spots on body
• In Japan and N.America the occurrence of this disease is higher can be due to mutations caused by Founder effect
• More severe form of XP-DeSanctis-Cacchione syndrome associated with neurological syndrome
• Treatment – skin creams that contain DNA repair enzymes in the form of liposomes

7. GENE CHROMOSOME FUNCTION OF PRODUCT
XPA 9 Dna damage recognition protein
XPB 2 3 5’ helicase
XPC 3 Dna damage recognition protein
XPD 19 5’ 3’ helicase
XPE 11 Dna damage recognition protein
XPF 16 Nuclease, 3’ incision
XPG 13 Nuclease, 5’ incision
XPV 6 Translesion DNA Polymersae η

8. COCKAYNE SYNDROME (NEIL DINGWALL
SYNDROME)
• Autosomal recessive disease
• Defective genes: XPD, XPG, XPB,CSA, CSB
• Deficient in the NER pathway
• CSA and CSB deficient cells are unable to repair cyclobutane pyramidine dimers induced by the action of ultraviolet (UV) light
on the template strand of actively transcribed genes
• Acute sensitivity to light
• implication: premature aging, demylination of neurons, dwarfism, microcephaly, hearing loss, brain shows prominent
calcification,kyphosis,arrested sexual development, subcutaneous fat loss
• Symptoms of CS can also occur in patients with XP
• Cockayne syndrome is divided into types I, II, and III based on the severity and age of onset of symptoms
• Severe form of CS- Cerebro-oculo-fasio- skeletal syndrome

9. Diagnosis
• Brain CT scanning in Cockayne syndrome patients may reveal calcifications and
cortical atrophy, atrophy of the central area of the cerebellum found in patients with
Cockayne syndrome could also result in the lack of muscle control, particularly
involuntary, and poor posture
• Prenatal evaluation is also possible. Amniotic fluid cell culturing is used to
demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation.
• In Cockayne syndrome patients, UV-irradiated cells show decreased DNA and RNA
synthesis

11. TRICHOTHIODYSTROPHY (TTD)
• Autosomal recessive disorder
• Defective gene – TTDA present in chromosome no: 6, ERCC2, ERCC3
• Mutation in these gene cause reduced amount of TF11H complex which impairs both DNA
repair and transcription
• Defect in NER pathway
• Symptoms : short stature, skeletal abnormalities, brittle hair, congenital cataract,mental
retardation
• 50% of the population have photosensitivity
• Prenatal diagnosis, based on measurement of DNA repair in trophoblasts or amniotic cells, is
available
• No specific treatment is available

12. TRIPLE A SYNDROME
• Autosomal recessive disorder.
• Three specific features : Achalasia, Addisons disease, Alacrima ( inability to secrete tears).
• Mutation in gene AAAS .
• The gene product ‘ ALADIN’ is a component of nuclear pore complex.
• Mutant ALADIN cause decreased nuclear import of aprataxin, a repair protein for DNA single
strand breaks and DNA ligase 1.
• These decrease in DNA repair proteins allow DNA damage to accumulate that trigger cell death.
• Nucleoporin ALADIN involved in spindle assembly also.

13. ATAXIA- TELANGIECTASIA
• Rare , inherited, neurodegenerative disease
• Affected gene – ATM in chromosome no: 11
• Defect in double stranded break repair pathway
• ATM serine/threonine kinase is recruited and activated by DNA double-strand
breaks. It phosphorylates several key proteins that initiate activation of the DNA
damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several
of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor
suppressors.
• ATM gene control cell divison and involved in DNA repair

15. SYMPTOMS
• characterized by progressive difficulty with coordinating movements (ataxia)
• Radiation sensitivity
• Affected children typically develop difficulty walking, problems with balance and hand coordination,
involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve
function (neuropathy).
• slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia)
• Small clusters of enlarged blood vessels called telangiectases, which occur in the eyes and on the
surface of the skin, are also characteristic of this condition.
• Affected individuals tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their
blood.
• Weakened immune system, chronic lung infection
• High risk of developing cancers like leukemia and lymphoma

16. DIAGNOSIS OF A-T , TREATMENT
• Elevated level of alpha feto protein in serum after 2 yrs of age
• Immunodeficiency with low level of immunoglobulins( IgG, IgA, IgE)
• Chromosomal instability( fragmented)
• Cerebellar atrophy – MRI scan
• Confirmatory test : deficiency of ATM protein in cultured blood cell or mutation in
both copies of ATM gene
• No specific treatment, can only reduce the severity of symptoms

17. FANCONI ANEMIA
• Rare inherited disorder
• Affected genes – FA ( 8 GENES, A-H, on 5 different chromosomes)
• Mutations in at least 8 genes can cause Fanconi anemia.
• Proteins produced from these genes are involved in a cell process known as the FA
pathway.
• FA pathway is activated when DNA replication is blocked due to DNA damage
• The FA pathway recruits certain proteins to the area of damage, which trigger DNA
repair so DNA replication can continue
• DNA damage- Interstrand crosslink

18. SYMPTOMS
• bone marrow failure, physical abnormalities, organ defects,
• Aplastic anemia, extreme tiredness, frequent infections and clotting problems
• People with Fanconi anemia may also develop myelodysplastic syndrome, a
condition in which immature blood cells fail to develop normally.
• Hypopigmentation –flat patches of skin darker than surrounding area
• Short stature, malformed thumbs, gastrointestinal abnormalities; heart defect
• Abnormalities of brain and spinal cord including hydrocephalus and microcephaly
• 10-30 % chance of developing cancers like acute myeloid leukemia

19. BLOOM SYNDROME
• Affected gene – BLM (chromosome no: 15), function –produce BLM RecQ helicase
• Double strand break reapir pathway affected
• chromosome breakage occurs more frequently in affected individuals
Symptoms
• short stature, skin rashs that develops after exposure to the sun, increasesd risk of cancer.
• sensitive to sun exposure, usually develop a butterfly-shaped patch of reddened skin across the nose and cheeks
• small clusters of enlarged blood vessels (telangiectases) often appear in the rash; telangiectases can also occur in the eyes
• Affected individuals have high-pitched voice, a long, narrow face; a small lower jaw; and prominent nose and ears.
• chronic obstructive pulmonary disease (COPD),
• Men with Bloom syndrome infertile.
• Women with the disorder generally have reduced fertility and experience menopause at an earlier age than usual.

20. WERNER SYNDROME ( ADULT PROGERIA)
• Autosomal recessive disorder
• Affected gene WRN in chrom no: 8, product: WRN RecQ helicase
• Defect in DNA repair of doubled stranded breaks
• Symptoms : chromosome instability, mental retardation, cancer prone
• At the level of gene expression, WRN protein deficiency causes changes in the
pattern of gene expression that markedly resemble those of normal old age.
• Premature aging symptoms: graying and loss of hair, senile cataract,
skin atrophy( wasting), atrophy of gonads leading to reduced fertilty

21. ROTHMUND – THOMSON SYNDROME
• Rare autosomal recessive
• mutations in the DNA helicase RECQL4 gene present in chr no: 8
• Cause error in homologous recombination (HR)-dependent double-strand break repair.
• Symptoms : juvenile cataract, saddle nose, congenital bone defects, sun sensitive rashes,
hypodontia( absence of teeth), osteocarcoma

22. NIJMEGAN BREAKAGE SYNDROME
• rare autosomal recessive ,congenital disorder causing chromosomal instability
• Mutated gene NSBI in chrom no : 8, involved in DNA double strand break repair
• Defect in homologus recombination repair
• NBS1 codes for a protein (nibrin) that has two major functions: (1) to stop the cell
cycle in the S phase, when there are errors in the cell DNA (2) to interact with
FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair
• Lack of functional nibrin can cause reduced potent immune cells

23. Symptoms
• Microcephaly, sloping forehead with prominent nose, short stature,
immunodeficiency ( low levels of IgA and IgG), radiation sensitivity
• No permanent cure

24. REFERENCE
 Cleaver, James E. "Cancer in xeroderma pigmentosum and related disorders of DNA repair." Nature Reviews Cancer
5.7 (2005): 564-573.
 Gerald karp, CELL AND MOLECULAR BIOLOGY, 5th edition.
 Jeppesen, Dennis Kjolhede, Vilhelm A. Bohr, and Tinna Stevnsner. "DNA repair deficiency in neurodegeneration."
Progress in neurobiology 94.2 (2011): 166-200.
 McKinnon, Peter J. "DNA repair deficiency and neurological disease." Nature Reviews Neuroscience 10.2 (2009): 100-
112.
 Snustad and Simmons, PRINCIPLES OF GENETICS,5th edition.
 T.A Brown, GENOME.
 Wikipedia
 www.geneticshomereference.com

25. THANK YOU