Genetic Basis Of Oral Diseases.docx

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 2) deletion

Shift nucleotide position to form different codons

CHROMOSOMAL MUTATIONS •

Large alteration in chromosome structure

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Readily visible microscopically→ Karyotyping

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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

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Autosomal Dominant, Autosomal recessive, Sex linked

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AUTOSOMAL DOMINANT → if one or two copies of gene bears a deleterious mutation (Eg: Hypodontia)

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Traced through family pedigree- Individuals with disease present in successive generations

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Equal number of males and females with disease

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Each affected individual has one parent with disease

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Over 200 autosomal dominant diseases known

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2.Autosomal Recessive •

Two abnormal copies of gene present

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900 autosomal recessive diseases known

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often in communities with consanguineous marriages

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↑ Probability of mating between 2 carriers

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both parents-carriers, child has 1 in 4 chance of disease

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Unaffected parents can have affected offspring

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Equal gender distribution

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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

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Incomplete penetrance – due to modifier genes / environmental factors (Eg: Schizophrenia, BPD)

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Penetrance → ALL OR NONE state

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Complete Penetrance –Neurofibromatosis 100% with mutation in NF1 gene have disease

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Incomplete Penetrance – familial Breast Cancer 80% with BRCA1 gene develop cancer

VARIABLE EXPRESSIVITY •

Variable expression of dominant disease

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range of signs and symptoms that can occur in different people with same genetic condition

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Allele for polydactylism –dominant – but can manifest as digit/ stub

unilateral/ bilateral trait;

Effect of modifier genes – interact with disease gene

SEX LINKED/X-LINKED DISEASES •

Mutation in 1 of more than 285 genes on X chromosome

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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

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Eg: Anhydrotic ectodermal dysplasia

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All female children of affected male are affected

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Children of affected female → 50% chance

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No male to male transmission (X chromo from mother only)

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X-linked recessive → only males affected

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Females(Carriers) → No/mild symptoms

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Mother asymptomatic carrier → son affected

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Occasionally → females affected → if normal X chromosome inactivation

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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

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Do not present well delineated Mendelian inheritance

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Tend to run in families

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Craniofacial malformations, tooth decay, periodontal disease, atherosclerosis, osteoporosis, hypertension, diabetes mellitus, peptic ulcers, clefts

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Dynamic interplay between regulatory and structural genes with environmental/ behavioural factors

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Cleft palate - Genes – MSX1, interferon regulatory factor 6 & their expression

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Environment – Protein energy malnutrition, Folic acid deficiency, alcohol, tobacco

GENDER BIOLOGY •

Sex chromosomes – not only for sex determination

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Profound influence on multigene disorders

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Gender differences in CAD, osteoporosis ( not just hormonal)

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Gender differences in drug response – absorption, metabolism

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Autoimmune diseases (Sjögren’s syndrome ,lupus erythematosus, scleroderma) – 80% females

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AIDS signs and symptoms develop at lower viral load than men

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Pharmacogenetics : genetic difference in drug metabolic pathways that affect individual response to drugs – therapeutic and adverse effects

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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

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Recurrent loss of chromosome 9,13,18

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Deletion on chromo 9p – dysplasia , carcinoma-in-situ

2) ONCOGENES

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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.

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Transcription factor c- myc - Overexpressed in OSCC associated with poorly diff tumours and poor prognosis

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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 editionGreenberg, 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