MOSAICISMMECHANISMS AND IMPACT ON THE DISEASE

ANA FILIPA FREITASINÊS FIGUEIREDO

MARIA INÊS

GONÇALVESMARIANA FERREIRA

FACULDADE DE MEDICINA DA UNIVERSIDADE DE COIMBRA1.º ANO MESTRADO INTEGRADO MEDICINA

BIOLOGIA CELULAR E MOLECULAR II

13TH MARCH 2013

SUMMARY Definition

Mechanism

Types Germinal Somatic Mixed

Associated Diseases

Impact on the Disease

Heteroplasmy

Clinical Cases Cancer Down Syndrome

Prenatal Diagnosis and Pseudomosaicism

References2

MOSAICISM – THE DEFINITION

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“MOSAICISM is a condition in which is notted the

presence of two or more different chromosomal

complements in the same tissue.” (Azevedo, C.; Sunkel, C.E., 2005)

This condition can affect any type of cells.

(Reproduced from: Read, A.; Strachan, T., 2011)

Non-disjunction

Anaphase lag

Premature centromere division

MECHANISM OF FORMATION

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MEIOSIS

OR

MITOSIS

MECHANISM OF FORMATION

COMPLETE PARTIAL

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NON-DISJUNCTION IN POST-ZYGOTIC MITOTIC DIVISION

(Reproduced from: Azevedo, C.; Sunkel, C.E., 2005)

TYPES OF MOSAICISM

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GERMINAL MOSAICISM

SOMATIC MOSAICISM

GERMINAL AND SOMATIC MOSAICISM

TYPES OF MOSAICISM

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GERMINAL MOSAICISM

• Assintomatic

• Only germinal cells are affected

• Could be transmitted to descendents

• Osteogenesis imperfecta type ll

• Turner syndrome

• Duchenne muscular distrophy

• Haemophylia

TYPES OF MOSAICISM

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SOMATIC MOSAICISM

• Sintomatic

• Somatic cells are affected

• It’s not inherited

• Cancer

• Neurofibrosis

• Heterochromia iridum

• Down syndrome

Reproduce from: Health Encyclopedia of URMC

SOMATIC VS. GERMINAL MOSAICISM

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(A) Hypothetical pedigree of Segmental neurofibromitosis type 1 (AD) and (below) molecular analysis showing somatic mosaicism.

(Reproduced from: Youssoufian, H. et al., 2002)

(B) Hypothetical pedigree and molecular analysis showing germ-line mosaicism in tuberous sclerosis (AD).

HOW TO DETECT MOSAICISM?

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Karyotype analysis Fluorescent in situ hybridization

(FISH) Array Comparative genomic

hybridization (array CGH)

Composite array results for mosaic deletions and duplications . Reproduced from [3]

Examples of FISH results on fetal ovarian cells using two chromosome 21-specific probes. a) Location of the probes near the end of the long arm of

chromosome 21. b) Normal cell nucleus showing two dual chromosome 21-specific signals. c, d) T21 cell nuclei showing three dual chromosome 21-specific signals.

Reproduced from [1]

MENDELIAN DISORDERS ASSOCIATED WITH MOSAICISM

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CLASSIFICATION DISORDER

Metabolic DisordersTyrosinemia Type I

Lesch-NyhanConradi-Hunermann-Happle

Immune DysfunctionAdenosine Deaminase Deficiency

Wiskott-Aldrich Syndrome

Clotting Disorders Haemophilias A and B

Skeletal DisordersMarfan Syndrome

Pseudoachondroplasia

Muscle DisordersDuchenne Musclar Dystrophy

Congenital Myotonic Dystrophy

Chromosomal InstabilityBloom SyndromeFanconi Anemia

Tumor SupressorNeurofibromatosis Types I and II

Tuberous Sclerosis

Skin DisordersBullous Ichthysiform Erythroderma

Incontinentia Pigmenti

Endocrine Disorders Androgen Insensitivity

Nervous-System Disorders Friedreich Ataxia

Table 1: Examples of additional Mendelian disorders associated with mosaicism Adapted from Youssoufian H. et. al. Human genetics and disease: Mechanisms and consequences of somatic mosaicism in humans. Nature Reviews Genetics 3, 748-758.

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[1] The mosaicism effects depend on the:

Stage where the mutation occurs

Nature of the abnormal chromosomes changes

Proportion between normal and abnormal cells

Nature of the affected tissues

MOSAICISM: THE IMPACT ON THE DISEASE

[1]Azevedo, C.; Sunkel, C.E., 2005

HETEROPLASMY

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Somatic mosaicism for mitochondrial disorders results from the random segregation of mutant and wild-type mitochondria during mitosis.

Daughter cells with different proportions mutated mitochondria.

The most severe mithocondrial diseases are heteroplasmic.

(Reproduced from: Youssoufian, H. et al., 2002)

CANCER

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Several recent studies have reported, that the probability of progression to cancer can depend on the degree of mosaicism in a tissue.

Cancer can be caused by mutations in genes that encode or control: transcription factors cell cycle checkpoint proteins growth factors repair proteins telomerase

The gene BUB1B, when mutant, causes a chromosomal instability that leads to cancer. it causes mosaic variegated aneuploidy, involving multiple different chromosomes and tissues.S.A. Frank / Journal of Theoretical Biology 223 (2003) 405–412

DOWN SYNDROME

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Free trisomy 21

Mosaic trisomy 21

Free trisomy 21 in mosaic

Meiotic error

Post-zygotic non-disjunction

Cell rescue

All cells are trisomic

Two different lines of cells:Normal and Trisomic

Robertsonian translocation Kariotype: 46, XX or 46, XY

THE MOSAICISM IMPACT ON DOWN SYNDROME

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Results in a highly variable clinical phenotype depending on: the tissues involved proportion of trisomic cells the sequence of events leading to

the mosaicism

THE MOSAICISM IMPACT ON DOWN SYNDROME

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LeukemiaAlzheimer’s DiseaseImmunodeficiencyInfections

Solid Cancers

Type 1 diabetesHypothyroidismAsthmaPremature aging

Increases

Decreases

According to Hultén et al. [2]

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Amniocentisis

Different cellular lines

2 or more individual cultures1 individual culture

Pseudomosaicism True Mosaicism

PRENATAL DIAGNOSIS AND PSEUDOMOSAICISM

REFERENCES

23/02/13: http://www.nature.com/scitable/topicpage/somatic-

mosaicism-and-chromosomal-disorders-867 http://www.chromosome18.org/TheConditions/Mos

aicism/tabid/490/Default.aspx http://www.upf.edu/cexs/actualitat/geneticmosaic.ht

ml#.USlI1qUtxLY http://www.molecularcytogenetics.org/content/1/1/

26 http://genomemedicine.com/content/pdf/gm168.pdf http://en.wikipedia.org/wiki/Mosaic_(genetics) http://users.rcn.com/jkimball.ma.ultranet/BiologyPa

ges/M/Mosaics.html http://www.med.uc.edu/embryology/chapter1/updat

es/mosaic.htm http://www.nlm.nih.gov/medlineplus/ency/article/0

01317.htm http://

books.google.pt/books?id=hSDrd9MfSCEC&pg=PA555&dq=mosaicism&hl=pt-PT&sa=X&ei=tU8pUaqILoiShgfuoIDIAw&ved=0CEsQ6AEwBQ#v=onepage&q=mosaicism&f=false

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REFERENCES

24/02/13: http://www.slideshare.net/rinaldowp/cnvs-e-mosaici

smo-durante-o-desenvovimento-somtico http://

www.geocities.ws/carolparada/biologiamolecular/mosaicismocromossomico.htm

http://www.google.pt/books?hl=pt-PT&lr=&id=jkw3y4DmrM4C&oi=fnd&pg=PA2&dq=mosaicismo+gen%C3%A9tico&ots=ZmNNg537Iz&sig=ZEp-bx-SUu_Ft_b63naGJy2ydRA&redir_esc=y#v=onepage&q=mosaicismo%20gen%C3%A9tico&f=false

http://laboratoriogene.info/DXPN/index.htm https://

www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=90&ContentID=P02132

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REFERENCES

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25/02/13 [1] Hultén MA, Patel SD, Tankimanova M, Westgren M, Papa-dogiannakis

N, Jonsson AM, Iwarsson E. On the origin of trisomy 21 Down syndrome. Mol. Cytogenet.2008;1:21. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564957/ )

[2] Hultén MA, Jonasson J, Nordgren A, Iwarsson E. On Germinal and Somatic Trisomy 21 Mosaicism: How Common is it, What are the Implications for Individual Carriers and How Does it Come About?. Curr Genomics. 2010 September; 11(6): 409–419. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018721/ )

[3] Conlin LK, Thiel BD, Bonnemann CG, Medne L, Ernst LM, Zackai EH, Deardorff MA, Krantz ID, Hakonarson H, Spinner NB. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet. 2010 April 1; 19(7): 1263–1275. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146011/ )

REFERENCES

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27/02/13: http://en.wikipedia.org/wiki/Heterochromia http://www.diagnosiprenatale.com/diagnosi-prenatale/mosaicismo-di

agnosi-prenatale.aspx http://downsyndrome.about.com/od/whatcausesdownsyndrome/a/m

osaic_ro.htm A. Paskulin, Giorgio; B. Lorenzen, Marina et all. (2011) Importance of the

fibroblast chromosomal analysis in suspected cases of mosaicism: experience of a clinical Genetics service. Revista Paulista de Pediatria.; 29(1):73-9.

Cunningham, Gary F.; Leveno, Kenneth J. et all. (2012) Williams Obstetrics. 23rd Edition. McGraw-Hill. Cap 12, P.275,276.

Pierce, Benjamin A.; (2004) Genética-Um Enfoque Conceitual. Cap 9, P.246-252.

Regateiro, Fernando J. (2007) Manual de Genética Médica. Cap IV. Rodríguez-Santiago, Benjamín; Malats, Núria et all. (2010) Mosaic

Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome. The American Journal of Human Genetics. July 9. P.87, 129–138.

REFERENCES

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03/03/13 Azevedo, C.; Sunkel, C.E. (2005). Meiose e Aneuploidia in Biologia Celular

e Molecular (pp.397-430). LIDEL-Edições Técnicas, Lisboa (Ed.) Lewis, Ricki. (2008) Human Genetics – Concepts and Applications; 8th

edition; chapters 5 (pp.96-98) and 18 (pp.367-373). McGraw-Hill. Read, A.; Strachan, T. (2011). Human Molecular Genetics; 4th edition;

chapter 3; Garland Science Youssoufian, H. et al. (2002). Mechanisms and consequences of

somatic mosaicism in humans (pp. 749-150). Nature Reviews Genetics 3.

Frank SA. Somatic mosaicism and cancer: inference based on a conditional Luria–Delbruck distribution. Department of Ecology and Evolutionary Biology, University of California. Journal of Theoretical Biology 223 (2003) 405–412 (http://stevefrank.org/reprints-pdf/03JTB-LD.pdf)

http://www.ncbi.nlm.nih.gov/omim http://www.uc.pt/fmuc/citogenetica/genomica/indicacoes

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QUESTIONS?