GENETIC BASIS OF ORAL DISEASES

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

DOUBLE FACTOR CROSS

 Ear lobe and hair colour (H-black, h-brown)
 ratio of phenotypes - 9:3:3:1
 CO-DOMINANCE - Alleles lack total dominant and recessive relationships – phenotype
of both alleles expressed in heterozygous condition – different from that of parents
(roan coat in horses- made of white and red individual hairs)
 INCOMPLETE DOMINANCE – Phenotype of heterozygote in between two homozygotes
– blending (pink snapdragons)
 MULTIPLE ALLELES – more than 2 alleles control a trait - ABO blood group
 Polygenic inheritance – interactions of several genes control a trait (height, hair colour)
 Pleiotropy – multiple effects of a gene on a phenotype (Marfans syndrome – connective
tissue disorder – many organs involved)
 LINKAGE - Genes for different characteristics are inherited together
 Autosomal linkage – 22 pairs of autosomes – genes for different traits when close
together on the same chromosome – inherited together- Chromosome 4
 Sex Linkage – Genes for different diseases linked to X or Y chromosomes
 Environmental influence on gene expression – internal (male pattern baldness due to
testosterone in males, freckles on sun exposure) or external (Diet for intelligence, height
etc)
 Epigenetics –Post translational alteration of gene function through methylation,
acetylation, sulfation or phosphorylation of histone and non-histone chromosomal
proteins without altering the nucleic acid sequence of the DNA
MUTATIONS
 Permanent alteration in DNA sequence that makes up a gene- 5 types
 Hereditary- inherited from parents, found in germ cells
 Acquired-later in life, found in somatic cells, caused by environmental factors
 De novo mutations – first time in a family due to mutations that occur in germ cells
alone/ shortly after fertilization
 Mosaicism- Somatic mutation in single cell early in embryonic development-only some
ells affected-may or may not cause disease
 Polymorphism – Common genetic alterations (>1% of population)-normal variant –
sometimes can increase the risk of disease
  Change in sequence of nucleic acids within DNA
 Triplet nucleotides (codons) code for different amino acids
A. SUBSTITUTION
1) Silent – no change in AA
2) Missense – single change in AA
3) Nonsense- form stop codons(TAA,TAG,TGA)
B. FRAMESHIFT
1) Insertion
Shift nucleotide position to form
2) deletion different codons

CHROMOSOMAL MUTATIONS
• Large alteration in chromosome structure
• Readily visible microscopically→ Karyotyping
• Macromolecular – affect many genes

CLASSIFICATION OF GENETIC DISORDERS

1. Single gene/Mendelian disorders – rare, familial (Eg:Hemophilia)
2. Chromosomal anomalies – sporadic (Eg:Down’s syndrome)
3. Multifactorial/Complex/polygenic disorders – environmental factors (Eg: Craniofacial
malformations, diabetes mellitus, hypertension, TMJ disorders, osteoporosis)
4. Acquired somatic genetic disease – cancers

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

SEX LINKED/X-LINKED DISEASES

• Mutation in 1 of more than 285 genes on X chromosome
• X-linked dominant :
 Affect both males and females
 Females less severely affected
 Inactivation of x chromosome carrying the disease allele in some females and
normal x chromosome in some females
• Eg: Anhydrotic ectodermal dysplasia
• All female children of affected male are affected
• Children of affected female → 50% chance
• No male to male transmission (X chromo from mother only)
• X-linked recessive → only males affected
• Females(Carriers) → No/mild symptoms
• Mother asymptomatic carrier → son affected
• Occasionally → females affected → if normal X chromosome inactivation
• Mnemonic – Hari Got A Dull Life & Miserable Wife
Hemophilia, G6PD deficiency, Agammaglobulinemia
Diabetes insipidus, Lysh Nyhan Syndrome
Muscular dystrophy, Wiskott Aldrich syndrome
2. CHROMOSOMAL DISEASES
A. INCORRECT CHROMOSOMAL NUMBER
 TRISOMY 21 (Down’s syndrome)-Aneuploidy
 TURNER’S SYNDROME –Women with 1 X chromosome
 KLINEFELTER’S SYNDROME – Men with 2 X chromosome
B. Chromosomal structural defects –Microdeletions
DiGeorge syndrome - T cell immunodeficiency- microdeletion in chromosome 22
C. Uniparental disomy – presence of 2 copies of a chromosome from 1 parent and none from
the other parent
 Leads to “genetic imprinting”-” Parent of origin differences”
 Prader Willi syndrome – deficiency of paternal contribution
 Angelman syndrome – deficiency of maternal contribution

MITOCHONDRIAL DISEASES
• Mitochondria exclusively inherited from mother
• Codons for mt DNA different from of nuclear DNA
• Eg: Mitochondrial encephalomyopathy / myoclonic epilepsy

COMPLEX HUMAN DISEASES

• Most common form of genetic disease
• Do not present well delineated Mendelian inheritance
• Tend to run in families
• Craniofacial malformations, tooth decay, periodontal disease, atherosclerosis,
osteoporosis, hypertension, diabetes mellitus, peptic ulcers, clefts
• Dynamic interplay between regulatory and structural genes with environmental/
behavioural factors
• Cleft palate - Genes – MSX1, interferon regulatory factor 6 & their expression
• Environment – Protein energy malnutrition, Folic acid deficiency, alcohol, tobacco
GENDER BIOLOGY
• Sex chromosomes – not only for sex determination
• Profound influence on multigene disorders
• Gender differences in CAD, osteoporosis ( not just hormonal)
• Gender differences in drug response – absorption, metabolism
• Autoimmune diseases (Sjögren’s syndrome ,lupus erythematosus, scleroderma) – 80%
females
• AIDS signs and symptoms develop at lower viral load than men
• Pharmacogenetics : genetic difference in drug metabolic pathways that affect individual
response to drugs – therapeutic and adverse effects
• Pharmacogenomics : genetic make-up affecting response to drugs- recently used term –
broader- used interchangeably

CRANIOFACIAL DYSMORPHOLOGY ASSOCIATED WITH CHROMOSOMAL

ABNORMALITIES
CRANIOFACIAL – ORAL-DENTAL MENDELIAN GENETIC DISEASES AND
DISORDERS
DENTAL DISEASES
MULTIFACTORIAL
 Dental caries, Periodontal disease, malocclusion – environmental factors play a
dominant role
 Genetic susceptibility cannot be ruled out – may not be a single gene effect – paucity of
research
TOOTH FEATURES
 TOOTH SIZE
 Both genes and environment – Polygenic
 Key tooth in each class –highest heritability (genetic)
 Maternal/ intrauterine environment in other teeth
 Size of first molar – more genetically determined than third molar
  TOOTH ERUPTION
 Both genes and environment – Polygenic
 Prenatal environmental factors – low birth weight
 TOOTH MORPHOLOGY
 Cusp of carabelli and Shovel shaped incisors – Polygenic in origin
 Adverse maternal environment – decrease in cusp size, increase in depth of pits
and fissures
DENTAL CARIES
 Caries – genetic +environment
 Environment – oral hygiene, diet, fluorides
 Caries susceptibility – likely to have genetic basis
 Twin studies – difference in caries experience rate
 Resemblance in caries experience in monozygous twins greater than dizygous twins
 Twins
 Smooth surface caries – under more genetic control than pit and fissure caries
 Oral flora – streptococci – show heritability
 Salivary flow, pH, amylase – show heritability
ORAL GENODERMATOSIS
Inherited monogenic disorders - skin manifestations

 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.

GENETICS AND ORAL CANCER

 Cancer – complex, multi process – alteration of genetic events
 3 – 6 somatic mutations are needed to transform a normal cell into its malignant
counterpart

Genetic damage in oral caner

Dominant changes Recessive changes

(gain in function) (loss of function)

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

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 codon into GUG, which encodes amino
acid valine rather than glutamic acid
PROSPECTS IN ORAL MEDICINE – FUTURE
• GENOMIC MEDICINE / PERSONALIZED MEDICINE
Clinical decision based on the knowledge of the
individual’s DNA sequence
• Salivomics – salivary biomarkers in diagnosis of oral diseases
• Genetic screening assays for oral and craniofacial disorders-to become specific,
sensitive, faster &cheaper
• Risk assessment to become an integral part of treatment
• More debate on legal / ethical issues of genetic screening
• Molecular biology – increasingly important for dental biofilms, implants
• Molecular pathogenesis of OSCC – advanced diagnostic and therapeutic approaches

FOR FURTHER READING

• Burket’s Oral medicine - 12th edition-
Greenberg, Glick, Ship
• Tyagi R . Oral Health Comm Dent 2008;2(3):55-61
• Kavitha B. IJDR. DOI: 10.4103/0970-9290.66646
• Pirmohamed M. Br J Clin Pharmacol. 2001 Oct; 52(4): 345–347