Transcript
GENETIC INSTABILITY SYNDROMES
H.MADHUMITHAI M.SC.HUMAN GENETICS
PRESENTED BY
• The stability of the cellular genome is constantly threatened by a variety of exogenous and endogenous mutagenic agents such as UV light, reactive oxygen species, etc.
• Cells protect their genome against carcinogenic alterations by using a complex network of “caretaker” proteins that function to maintain the integrity of the cellular chromosomes.
• Inherited defects in these caretaker genes are the cause of genomic instability syndromes in humans, such as Fanconi Anemia or Bloom syndrome, characterized by a highly elevated risk to develop certain types of cancer.
GENOMIC INSTABILITY
• An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.
• DNA damage -
Cellular metabolismRoutine errors in DNA replication & recombination
We study these diseases to understand and discover novel mechanisms important to control and suppress cancer susceptibility.
Response system -
induces cell cycle arrest
activates the appropriate DNA repair pathway
induces apoptosis
Mutations in the genes that encode DNA damage response proteins can result in a number of genomic instability syndromes, disorders that often result in a heightened predisposition to cancer.
COMMON ERRORS IN DNA REPAIR MECHANISM
• Loss of a bases- Results in apurinic/apyrimidinic (AP) sites (abasic sites); • Base modifications-Alkylations or deamidations
Causes Errors
Photo damage by UV light CPDsPyrimidine(6-4) Purimidone photoproducts(6-4PPs)
Chemical agents & ROS Modify bases
Replication errors & base conversions
Mismatch nucleotide pairs
Failures in normal DNA metabolismIonizing radiation
Single strand and double strand breaks
MISMATCHESLOOPS
Removes Incorrect/damaged bases
HRR:Synthesis- dependent strand annealingSingle- strand annealingNHEJ:Direct modification & ligation of 2 DNA ends in DSB.
Recognizes abnormal structures
DOUBLE STRANDED BREAKS
• DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally can lead to cancer
• defects in the genes encoding ATM, NBN (NBS1), BRCA1, FANCD2, BLM, TP53, CDS1/CHK2, and others, can cause cancer and genomic instability disorders.
FANCONI ANEMIA
MUTATION
• Fanconi anemia (FA), is a rare, blood disorder that leads to bone marrow failure.
• Acquired or Inherited• Prevents bone marrow from making
enough new blood• Can affect many of your body's
organs, tissues, and systems• Autosomal recessive disorder• Heterozygote frequency- 1 in 300
FANCONI ANEMIA
Skin hyperpigmentationIncreased café-au-lait spotsShort statureSkeletal abnormalitiesHypogonadism in malesRenal anomalies
Microcephaly or micrognathiaLow birth weightRetardationEar abnormalities GI tract abnormalitiesCongenital heart disease
FA- PHYSICAL ABNORMALITIES
Deficient in their ability to excise UV-induced pyrimidine dimers from their DNADNA crosslink repair deficiency is responsible for chromosomal damage in this disorder. Cellular defect in FA results in chromosomal instability, hypersensitivity to DNA damage, and hyper mutability thus predisposing to leukemia as a multistep processFanconi anemia had spontaneous genetic reversion correcting the FA mutations.
FA- MOLECULAR GENETICS
MHF1 and MHF2 - work together to bind to specific DNA structures and are "indispensable for the functional integrity of the FA pathway.“
The proteins were identified working through a specific core component protein of the FA pathway called FANCM, one of eight currently known to make up the FA core complex.
MHF1 and MHF2 help FANCM prevent or repair Interstrand crosslinks, which if unresolved can lead to cell defects and disease
Loss of MHF1 alone disrupts normal function of the entire FA pathway and suppression of MHF1 destabilized FANCM and caused increased chromosome aberrations.
SYNDROME
GENE LOCATION
PRODUCT
Fanconi A FANC A 16q 243 DNA repair
Fanconi C FANC C 9q 223 DNA repair
Fanconi D FANC D 3p22- p26
DNA repair
Fanconi E FANC E 6p21- p22
DNA repair
Fanconi G FANC G 9p13 Post replication repair
In vitro enhancement of chromosome breakage by DEB and mitomycin C
•
DIAGNOSIS
Bone Marrow Transplantation from an HLA compatible sibling.Gene therapy Published studies indicate it is possible to insert the cloned FANC-C and FANC-A gene into hematopoietic FA stem cells and provide protection against clastogenic agents.
TREATMENT
MUTATION
ATAXIA TELANGIECTASIA
Immunodeficiency disorderAutosomal recessive disorderAffect central nervous & immune systemsCerebellar damageImmunodeficiency
Radiation sensitivityCell cycle abnormalitiesChromosomal instabilityPredisposition to leukemias & lymphomasIncreased risk breast cancer
ATAXIA TELANGIECTASIA
Sole gene responsible for this disorder 66 exons 11q22-23 12kbp Protein- 350 kD ATMs activity increases following DSBs
ATM GENE
Activation of ATM gene
• The activation of atm is only partially understood, but it involves auto or trans phosphorylation of serine in response to DNA DSBs and may require protein phosphatase 5 activity.
• Breaks in genome leading to rapid activation of entire ATM- chain reaction occurs- active ATM monomers released- phosphorylate inactive ATM dimers.
• Phosphorylation of TP53 by ATM occurs on Ser15
• Stabilization of Tp53 is induced by ATM
• MDM2- negative regulator- inhibits p53
DIAGNOSIS recurrent infections and typical immunologic findings Elevation of serum alpha- fetoprotein levels Micronucleus test Detection of the protein (ATM) made by the A-T gene using a western blot Measurement of cellular damage (cell death or chromosomal breakage) after exposure of cells to x-rays in the laboratory Sequencing (reading the spelling) of the A-T gene (ATM)
NBSNBS/
MRE11/RAD50
MUTATION
NIJIMEGEN BREAKAGE SYNDROME
• Rare autosomal recessive disorder• Microcephaly• A distinct facial appearance• Short stature• Immunodeficiency• Radiation sensitivity• A strong predisposition to lymphoid
malignancy
CAUSES
• Nijmegen breakage syndrome is caused by mutations in the NBN/NBS1 gene located at 8q21.
• The entire gene consists of 16 exons and spans a DNA region of more than 50 kilobases.
• NBN gene product(nibrin)- interact-, hMre11 and Rad50.
• Nibrin- regulates the activity of the M/R/N protein complex- end-processing of both physiological and mutagenic DNA double-strand breaks (DSBs).
• DNA DSBs occur as intermediates in physiological events, such as recombination during early B- and T-cell development and immunoglobulin class switch in mature B cells, but most frequently are generated by mutagenic agents such as IR and radiomimetic chemicals
• Consanguineous matings have been reported.
DIAGNOSIS• The diagnosis is based on the
characteristic phenotype and laboratory results.
• Laboratory studies helpful in diagnosing Nijmegen breakage syndrome include cytogenetic analysis, an evaluation of humoral and cellular immunity, and radiation-sensitivity testing.
• Molecular genetic analysis enables definite confirmation.
• Serum alpha-fetoprotein levels are within the reference range in patients with Nijmegen breakage syndrome
TREATMENT
• No specific therapy is available for Nijmegen breakage syndrome (NBS).
Mortality/Morbidity
• Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.
• Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency, and bone marrow aplasia (aplastic anemia).
MUTATION
BLOOM SYNDROME
• Rare autosomal recessive disorder • Characterized by telangiectases and
photosensitivity• growth deficiency of prenatal onset• Variable degrees of
immunodeficiency• Increased susceptibility to neoplasms
of many sites and types. • The New York dermatologist David
Bloom first described the syndrome in 1954.
CAUSES
• Mutation – BLM gene- Chromosome 15q26.1
• DNA helicase activity and functions in the maintenance of genomic stability
• Increased sister chromatid exchanges and chromosomal instability also occur
• BLM variants & proteins that form complexes with BLM (eg, TOP3A, RMI1)
• Increases cancer risk• Mutation- DNA ligase I gene- primary
metabolic defect in Bloom
LABORATORY STUDIES
• Chromosome study- blood and skin cells show a characteristic pattern of chromosome breakage and rearrangement.
• Testing for chromosome instability- includes the presence of quadriradicals and increased sister chromatid exchanges
• Decreased immunoglobulin A and immunoglobulin M levels
PROGNOSIS
• Increased risk of premature death in the second or third decade occurs secondary to malignancies.
• Various types of leukemia develop at a mean age of 22 years.
• Patients who survive beyond age 22 years develop solid tumors at an average age of 35 years. Fortunately, these tumors are sensitive to chemotherapy and radiotherapy.
ROTHMUND THOMSON SYNDROME
• poikiloderma congenitale• photosensitivity and
poikilodermatous skin changes• juvenile cataracts• skeletal dysplasias• predisposition to
osteosarcoma and skin cancer.
CAUSES
• Mutations- RECQL4 gene- Chromosome 8q24
• Encodes a RecQ DNA helicase.• RecQ helicases - DNA replication
and repair• Essential for the maintenance of
genomic stability• Presence of truncating, loss-of-
function mutations of the RECQL4 gene - development of skeletal abnormalities and osteosarcoma.
Differential Diagnoses & Workup
• Bloom Syndrome (Congenital Telangiectatic Erythema)
• Dyskeratosis Congenita• Erythropoietic Protoporphyria• Lupus Erythematosus, Acute
Baseline skeletal radiographs of the long bones by age 5 -high frequency of skeletal dysplasias
WERNER SYNDROME
• Otto Werner originally defined Werner syndrome (WS) in 1904
• WS is also known as progeria adultorum, progeria of the adult, and pangeria.
• Most common of the premature aging disorders
• Autosomal recessive disorder that affects connective tissue throughout the body.
CAUSES
• Caused by a mutation at the WS gene (WRN) locus, which belongs to the family of RecQ helicases
• involved in the response to DNA damage during replication, as well as in the transcription processes.
• Excessive synthesis of collagen types I and III
• Collagenase level is also increased several times.
FREQUENCY
• WS is a rare disorder. • United States- 1 case in 1
million individuals.• WS has no specific laboratory
abnormalities
NUCLEOTIDE EXCISION REPAIR
Damage recognitionBinding of a multi-protein complex at the damaged siteDouble incision of the damaged strand several nucleotides away from the damaged site, on both the 5' and 3' sidesRemoval of the damage-containing oligonucleotide from between the two nicksFilling in of the resulting gap by a DNA polymeraseLigation
XERODERMA PIGMENTOSUMCOCAYNE’S SYNDROME
XERODERMA PIGMENTOSUM
• severe light sensitivity• frequent neurological defects• severe pigmentation
irregularities• early onset of skin cancer at
high incidence• elevated frequency of other
forms of cancer
Frequency
• United States- 1 case per 250,000 population. Group XPC is the most common form in the United States.
Laboratory Studies
• No consistent routine laboratory abnormalities are present in xeroderma pigmentosum patients.
• The diagnosis of xeroderma pigmentosum can be established with studies performed in specialized laboratories.
• These studies include cellular hypersensitivity to UV radiation and chromosomal breakage studies, complementation studies, and gene sequencing to identify the specific gene complementation group.
TREATMENT
• The goal of treatment is to protect the patient from sunlight
• The use of sunscreens in conjunction with other sun-avoidance methods (eg, protective clothing, hats, eyewear) can minimize UV-induced damage in patients with xeroderma pigmentosum.
COCKAYNE’S SYNDROME
Features
light sensitivity in some cases neurological abnormalities premature aging of some tissues facial and limb abnormalities dwarfism thinning of the skin and hair sunken eyes a stooped standing posture
Complications
Mental RetardationGrowth failure Progressive pigmentary retinopathy Sensorineural hearing loss Joint contractures and ataxia Hypertension Photosensitivity Premature death
CS- TYPES
Cockayne syndrome type 1- the classic form; Cockayne syndrome type 2- a more severe form with symptoms present at birth Cockayne syndrome type 3- a milder form; xeroderma pigmentosa–Cockayne syndrome (XP-CS).
FREQUENCY
US- 1 in 2,50,000 LIVE BIRTHS
CAUSES
• CKN1- defect-CSA gene or ERCC8- chromosome 5.
• Cells- ERCC8 mutations - hypersensitive to UV light.
• They do not recover the ability to synthesize RNA .
• They cannot remove and degrade DNA lesions from strands that have active transcription.
• CS type 2- Mutations in the DNA excision repair gene CSB or ERCC6)- Chromosome 10q11
• Encodes helicase- DNA unwinding function.
• Mutations-• deletion of exon 4• an amino acid substitution at the
106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein
• large deletion in the upstream region, including exon 1 of the CSA gene.
• a missense mutation (A205P) and a nonsense (E13X) mutation have been identified
• single nucleotide polymorphism in CKN1.
LABORATORY STUDIES
• Chromosome breakage studies and DNA mutation analysis are necessary to exclude Bloom syndrome and xeroderma pigmentosum.• Cultured skin fibroblasts of
patients with CKN1 lack the ability to form colonies when subjected to UV irradiation
IMAGING STUDIES
• CT scan or MRI findings include increased ventricular size, cerebral atrophy, white matter abnormalities, and normal pressure hydrocephaly. • Skeletal radiographs depict
vertebral body and pelvic abnormalities.
SUMMARY
THANK YOU
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