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DR.C.KRITHIKA
Vice principal, Prof &Head
Oral Medicine & Radiology
Thai Moogambigai Dental College & Hospital
INTRODUCTION
WHY THIS TOPIC?
Hypodontia is caused by mutation in the transcription factor of MSX1gene and can
follow autosomal dominant, autosomal recessive or X-linked patterns of inheritance,
with remarkable variation in both penetrance and expressivity
Deletion in the long arm of Chromosome 5 is seen in Gardner’s syndrome
Sickle cell disease is caused by a single point mutation (a missense mutation) in the 6th
codon of the beta-Hb gene that converts a GAG into GUG, which encodes amino acid
valine rather than glutamic acid
WHAT’S IN STORE…
TERMINOLOGIES
CHROMOSOME/ GENE/ DNA
Protein synthesis – Transcription/ translation
Inheritance – Dominant, recessive, others
Mutations – Gene chromosome
Classification of genetic disorders
Mendelian disorers/ Chromosomal disorders
List of Orofacial genetic disorders
Genetics in Dental caries, Oral cancer
Future prospects
TERMINOLOGIES
Genetics - Branch of science that studies how characteristics of organisms are inherited
DNA – found in chromosomes within the nucleus of the cell or within mitochondria in
cytoplasm
Gene is a discrete unit of DNA which has the necessary info to code for a protein &
regulate its expression
Characteristics are a result of proteins at work
Gene is related to the characteristic of an organism
Alleles- different versions of the same gene – responsible for different versions of the
same characteristic
Human Genome project(2004)- exhaustive database- 20K-25K genes within nucleus of
each somatic cell, 9 in mitochondria
PROTEIN SYNTHESIS
Transcription (in nucleus)- making RNA from DNA - Use DNA as template to synthesize
m RNA
Translation (in cytoplasm) – make protein from RNA
Amino acids assembled correctly to form proteins
Start sequence, Promoter sequence, Stop sequence
PROTEIN TYPES
STRUCTURAL PROTEINS
Genetically different collagens
keratins, globins
amelogenins, enamelins,
metalloproteinases,albumins,
Dentin sialoglycoproteins / phosphoproteins
REGULATORY PROTEINS
Transcription factors – Proteins that bind to DNA sequence – regulate transcription of
genes
Growth factors- secreted molecules – interact with receptors- influence cellular
behaviour
INHERITANCE
Sperm and eggs haploid – have 1 allele for a gene
Zygote – unique combination of genetic info
Genotype- combination of alleles in organism
Phenotype – how it is expressed outwardly
Homozygous – if both alleles are the same
Heterozygous – if both alleles are different
Dominant allele masks the recessive allele in the phenotype of an organism
CHROMOSOMAL MUTATIONS
• Large alteration in chromosome structure
• Readily visible microscopically→ Karyotyping
• Macromolecular – affect many genes
1. MENDELIAN DISORDERS
• INHERITED - single gene mutation
• Autosomal Dominant, Autosomal recessive, Sex linked
• AUTOSOMAL DOMINANT → if one or two copies of gene bears a deleterious mutation
(Eg: Hypodontia)
• Traced through family pedigree- Individuals with disease present in successive
generations
• Equal number of males and females with disease
• Each affected individual has one parent with disease
• Over 200 autosomal dominant diseases known
•
2.Autosomal Recessive
• Two abnormal copies of gene present
• 900 autosomal recessive diseases known
• often in communities with consanguineous marriages
• ↑ Probability of mating between 2 carriers
• both parents-carriers, child has 1 in 4 chance of disease
• Unaffected parents can have affected offspring
• Equal gender distribution
• If both parents are affected, all offsprings are affected
PENETRANCE
• Even though dominant disease should be apparent in all carriers → True only when
disease is 100% penetrant
• Incomplete penetrance – due to modifier genes / environmental factors (Eg:
Schizophrenia, BPD)
• Penetrance → ALL OR NONE state
• Complete Penetrance –Neurofibromatosis
100% with mutation in NF1 gene have disease
• Incomplete Penetrance – familial Breast Cancer
80% with BRCA1 gene develop cancer
VARIABLE EXPRESSIVITY
• Variable expression of dominant disease
• range of signs and symptoms that can occur in different people with same genetic
condition
• Allele for polydactylism –dominant – but can manifest as unilateral/ bilateral trait;
digit/ stub
Effect of modifier genes – interact with disease gene
MITOCHONDRIAL DISEASES
• Mitochondria exclusively inherited from mother
• Codons for mt DNA different from of nuclear DNA
• Eg: Mitochondrial encephalomyopathy / myoclonic epilepsy
Mutational analysis not only helps in genetic counselling and to make DNA-based prenatal
diagnosis in high risk families, it is also useful in developing the targeted therapeutic options
oral findings are distinct and may provide the first clue of an underlying genetic diagnosis.
1) CYTOGENETICS
• Human oral cancer - > 63 karyotypes
• Recurrent loss of chromosome 9,13,18
• Deletion on chromo 9p – dysplasia , carcinoma-in-situ
2) ONCOGENES
• Mutated version of regulated normal counterpart (proto oncogene) get activated by
point mutations and gene rearrangements in one gene copy
ras, c-myc, in c – 2 - replicated
3) GROWTH FACTOR
• TGF - ὰ overexpressed – epithelial hyperplasia , inflammation
4) CELL SURFACE RECEPTORS:
• EGFR – bio receptor for TGF - ὰ and EGF – overexpressed.
5) TRANSCRIPTIONAL FACTORS:
• Proteins that regulate expression of other genes.
• Transcription factor c- myc - Overexpressed in OSCC associated with poorly diff tumours
and poor prognosis
• PRAD-1 (cyclin D)-cell cycle promoter amplified in HNSCC
TUMOUR SUPPRESSOR GENES
• Negative regulatory controls – lost during tumour formation
• Functional loss of multiple TSG – major event in carcinogenesis
• TSGs – inactivated by point mutations, deletions and rearrangements in both copies –
“two- hit” fashion
• TSG P53 – mutated in 70% of adult solid tumours
• Normal P53- regulator of DNA synthesis (blocks cell division of genomic damage
detected and stimulates DNA repair)
• Mutated P53 – allows tumour to pass through G1-S boundary, propagate genetic
alterations.
• Transition of superficial to invasive carcinoma
• P53 mutation due to point mutation or deletion
• P53 interacts with oncogenic protein E6 of HPV – leading to rapid degradation of P53.
• Other TSG – DOC – 1 ,TSP - 1