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1

Triploidy-

is a multiple of haploid number- 1 too many of each chromosome
- Severe intrauterine growth retardation
- Macrocephaly
- Total syndactyly of 3rd and 4th fingers
- CNS, heart and renal defects
- Dysplastic cranial bones
- Eye defects
- Cleft L/P
- Malformed ears
- Micrognathia
- Genital anomalies
- Rarely spinobifida, hypotonicity and atrophy of cerebral cortes and corpus callosum

2

nullisomy-

absence of a homolog pair (2N-2)

3

monosomy-

1 too few chromosomes (2N-1)
- Turner’s syndrome- monosomy X-
- Only monosomy compatible with life

4

trisomy-

1 too many chromosomes (2N+1)- result of nondisjunction- can happen mainly in the female cell line during early stage of mitotic division, mosaic division can happen but has minor effect
- Klinefelter’s syndrome male with XXY
o 1/1500
o Variance- XXXY, XXXXY etc
o Low fertility
o Poor beard growth
Trisomy 13, 18, 21

5

Klinefelter’s syndrome

male with XXY
o 1/1500
o Variance- XXXY, XXXXY etc
o Low fertility
o Poor beard growth

6

Meiotic divisions in oogenesis/spermatogenesis


- Importance
o Recombination of genes through crossing overvatiation
o Constancy of chrom #-->haploid gametes
o Random assortment of maternal and paternal chrom

7

Oocyte

- begins Meiosis I prior to birth
- During dictyotene stage of Prophase I, division is arrested
- Follicular cells secrete “oocyte maturation factor” that keeps oocyte suspended in this phase for up to 45 years
- At ovulation, the 1st meiotic division is competed of primary Oocyte forming secondary oocyte and 1st polar body
- The first polar body will be expelled and the nucleus starts 2nd meiotic division, but stops in metaphase until fertilization
- First polar body undergoes meiosis II as well, forming 2 more polar bodies
- After fertilization 2nd polar body is expelled, and 2nd meiotic division completes to form ovum/zygote

8

Sperm

- Mitotic division of primordial germ cell forming primary spermocyte (diploid)
- Meiosis I creates 2 haploid secondary spermatocytes
- Meiosis II then forms 4 haploid spermatids
- 4 spermatids undergo spermiogenesis and form sperm
o 4 changes in spermiogenesis
o 1- most of cytoplasm is shed
o Formation of neck, middle piece and tail
o Condensation of nucleus
o Formation of acrosome

9

- Results of fertilization

o 2nd meiotic division completed
o Restores diploid number
o Variation of species
o Sex determination
o Initiates cleavage
 The 1st division
 Continues with the cell number doubling every division
 Compaction: Zygote doesn’t increase in size to the cell become progressively smaller
 Outside of zygote has bulges from rapid growth of cells=mulberry appearance=morula stage at 7 days
 Enters uterus

10

Epigenetics, Major mechanisms

- Definition: changes in gene expression without changes at DNA sequence
o DNA methylation (imprinting) and Chromatin modifications are the only with associations with epigenetics
o Heritable trait
o Dosage dependent
o Inheritance pattern mostly random

11

- Epigenetics and cellular functions

o Organization of chromatin
o Gene activation
o Gene silencing
o Silencing retrotransposal elements
o X-chromosome inactivation
o Maternal/paternal signature
o Reprogramming (iPS-induced pluripotent stem cells)
 Epigenetics determines whether the neural crest cells will be skin…..etc…

12

- Genes involved in epigenetics:

o DNMT1/2/3: methyl transferase
 Methylation of cytosine-essential for life
o MeCP2- methylated cytosine binding proteins-recognize the methylated cytosine and silence chromatin
 Also recruit HDAC’s that will also silence chromatin
o SWI/SNF- huge protein complexes able to twist, evict, change the order of chromatin- can completely remove or add histones- like powerful bodyguards
o HDAC- histone deacetylase- proteins that remove the acetyl group from histones- essential for life
 Cause deactivation of the chromatin
 They are recruited by MeCP2
o HAT- histone acetyltransferase- opposite of HDAC- it adds acetyl group and activates chromatin
o PcG/TrxG- polychrome G and Trithorax G- PcG recognize the methylated cytosines and silence the chromatin or trithorax G does the opposite and recognizes the active chromatin and keeps it that way

13

Role of apoptosis in development of lip/palate

- P63 important factor
- 3 possibilities- migration, apoptosis, or EMT
P63- and apoptosis- they think this is important to allow fusion of the LNP and maxillary prominences
-Pbx1 and 2 are involved in apoptosis, so believe this is important for palate development

-Disruption in any of these factors can lead to CLP
IRF6, AP2a, Lef1, K1, p63, Wnt, & k14
BMP, FGF, SHH and WNT- all important in epithelial development- they are signaling factors that need to be secreted from ectoderm to indue the transcription factors
Then the TF’s have to feedback to ectoderm to verify they got the signal to form the dental placode

14

Acrocentric-

chromosomes with very short p Arm-
- 13, 14, 15, 21, 22
- Genes that are in acro portion that can be lost----a lot of ribosomal DNA
- Can produce dicentric and acentric chromosomes through robertsonian translocation

15

Robertsonian translocation

- Leads to aneuploidy
o Monosomy and trisomy (13, 21 and 18)
- Acrocentric chromosomes exchange material on their p arms
- No pathological consequence, but their offspring may be affected by producing unbalanced gametes

16

Dynamic mutations

- Trinucleotide repeats
o Fragile X syndrome
o HD
o Common features of trinucleotide repeat diseases
 Anticipation
• Increase in repeat length correlates with increased severity and earlier onset
 Pre-mutation carriers are usually asymptomatic
• -premutations are unstable and can expand in one generation to a full mutation
• Germline specific expansion
o Fragile X expansion occurs in femaile
o HD expansion occurs in female
- Simple tandem repeats (STRs)

17

o Fragile X syndrome

 X-linked mental retardation
 Discovered in 1969
 Silencing of Fragile X mental retardation 2 (FMR1) 5’UTR methylation CpGG
 Fragment of BAC clone
 Fragment contained variable CGG repeat
 Pre-mutation 50 to 200 repeats
• Female carriers at risk for premature ovarian failure
• Male carriers at risk for fragile X assoc. with tremor/ataxia syndrome
 Full mutation>200 repeats
• Severity is dependent on somatic mosaicism and methylation
- Undergo dynamic mutation due to replication slippage
o change (expansion or contraction) can occur in one generation
o imperfect repeats appear to be more stable
o trinucleotide repeats appear to be the most dynamic

18

o HD

 All have CAG repeats in open reading frame
• Polyglutamine disease
• Are dominantly inherited
• Neurons are aggregate sensitive
• All involve degeneration of different neuron populations
• Aggregates of PolyQ protiens found in cells
• PolyQ expansion causes gain of function

19

- non-syndromic

o no other phenotype
o non-mendelian complex (spontaneous mutation)
o common (1/700)
o subjects have altered brain tissue distribution
 anterior- excess gray matter=thick cortex
 posterior-deficit in white matter
 cerebellum- decreased volume
 associated with social dysfunction – from volume of ventral frontal cortex

20

o genes involved in non-syndromic CLP

 IRF6, TGFA, MSX1, PVRL1, TGFB3, RARA, BCL3, CRISPLD2, SUMO1, MMP3, 8q24 locus, 17q22 locus, GREM1 and others, WNT signaling pathway (WNT3)
 TGFA- transforming growth factor alpha
• Taq I polymorphism
• Modifier gene- smoking and gene interaction
• Gene interaction with other SNPs and IRF6
 TGFB3
• Genetic heterogeneity and this gene may contribute in Asian population

21

o Environmental factors of CLP

 Nutrition
• Folate- MTHFR C667T involved in folatemet
 Hyperthermia
 Stress
 Obesity
 Occupational exposures
 Ionizing radiation
 infection

22

- Syndromes assoc. with clefting

o Holoprosencephaly- GLI2, SHH, SIX3
o Van der Woude/popliteal pterygium – IRF6
o Crouzon- FGFR2
o Apert- FGFR2
o Gorlin- PTCH1
o CLP- ectodermal dysplasia- PVRL1
o Tetra-amelia with CLP- WNT3
o Pierre Robin- SOX9
o X-linked CP and ankyloglossia- TBX22
o Treacher Collins- TCOF1
o Loeys-Dietz- TDFBR2
o Saethre Chotzen- TWIST1
o Wolf-Hirschorn syndrome- MSX1 at 4p16.3 (deletion at 16.3

23

Gene classes in CLP

- IRF6
- MSX1

24

CLP associated syndromes/epidemiology of

May result from disturbances at any stage:
- inadequate composition of palatal matrix
- delayed or failed shelf elevation
- inadequate disappearance of medial epithelial seam
- failure of mesenchymal consolidation and differentiation
- defective shelf fusion

25

Van der Woudes syndrome!!!

- Lip pits
- Autosomal dominant
- Rare (1/30,000)
- 70% have VWS exonic mutation
- Have problem with wound healing
- Mutation in IRF6 gene
o Missense mutation in functional domain
 Clusters at DNA binding domain and protein binding domain
o Truncation (nonsense) mutations evenly distributed
 Normally loss of function and cause RNA to decay

26

Causes of non-syndromic CLP

- Gene-gene interactions
- Gene-environment interactions
- Environmental factors

27

Link between tooth agenesis and colon cancer

- WNT’s and FGF;s
- AXIN2 mutations cause familial tooth agenesis and colorectal cancer predisposition
- CDH1- cleft L/P and cadherin mutations in families with hereditary diffuse gastric cancer
o Show cleft on one side and tooth agenesis on the other

28

• Penetrance:

Percentage (%) of affected individuals that carry the same mutation


29

• Expressivity:

Variation in the severity of a phenotype

30

• Sensitivity

– proportion of affected individuals correctly identified
• High sensitivity – low false negative rate