How Do Mutations Affect Health and Tooth Development Flashcards
continuum of diseases
environmental to genetic
The new HGMD professional release becomes available with a total of 170,118 — —
mutation entries
Loss-of-function mutation
Absence results in dysfunction
what do loss of function mutations result in?
less or no function of certain proteins
loss of function mutations constitute many — — cases in enzyme deficiency
autosomal recessive
two subtypes of loss of function
halpoinsuffciency
dominant negative
haploinsufficiency
reduced gene dosage is not sufficient to permit the cell to function properly
example of haploinsufficiency
Marfan syndrome with fibrillar mutation
dominant negative
A mutation whose gene product adversely affects (like an antagonist) the normal,
wild-type gene product within the same cell, usually by dimerizing (combining)
with it
In cases of polymeric molecules, such as collagen, dominant negative
mutations are often more
deleterious than mutations causing the production of
no gene product (cancer)
example of dominant negative
osteogenesis imperfecta
with dominant negative, the mutant protein is happy, but
annoying and disturbing other good protein function
Gain-of-function mutation
Increased function results in dysfunction
with gain of function mutations, mutations in certain genes gain a
new and abnormal function of the protein
example of gain of function mutation (2)
Charcot-Marie-Tooth sensory neuropathy, Cherubism
Over 300 genes identified that have
mutations associated with (3)
tooth patterning,
morphogenesis defects and cell differentiation defects
As a collective group craniofacial genetic
diseases are the
most common, 1/3 of diseases involve the craniofacial region
Double Bar indicates
consanguineous mating
— — diseases often present in
consanguineous marriages
Autosomal recessive
—- is a deeply rooted social trend among one-fifth of the world population
mostly residing in the Middle East, West Asia and North Africa, as well as among
emigrants from these communities now residing in North America, Europe and Australia
Consanguinity
The developmental signaling pathways that drive
tooth development are also critical in the
development of many other organs
Tooth developmental defects should perhaps be
thought of as a
potential risk factor for other
diseases that manifest later in life
genetic diseases and the dentition (6)
malocclusion syndromes craniofacial malformations bone mass traits tooth genesis tooth movement tooth development disorders
malocclusion syndromes (3)
– Pierre-Robin
– Treacher Collins
– Marfan syndrome
Craniofacial malformations (4)
– Crouson
– Apert
– Pfeiffer
– Clefting syndromes (lip and palate)
Bone Mass Traits (3)
– Sclerosteosis and van Buschem’s
– High Bone Mass and OPPG
– Paget’s Disease
Tooth Development Disorders (2)
– Dentinogenesis Imperfecta
– Amelogenesis Imperfecta
symptoms of ectodermal dysplasia
- Abnormal nails
- Abnormal and missing teeth
- Absent or very thin hair
- Absent tears (occasional)
- Decreased skin color (pigment)
- Foul-smelling nasal discharge
- Heat intolerance
- Inability to sweat
- Large forehead
- Light coloring
- Lower-than-normal number of teeth
- Low nasal bridge
- Poor temperature regulation
- Thin hair
- Thin skin
- – — is fairly common, but
- – — — is rare
Tooth impaction
multiple impacted teeth
supernumerary teeth (2)
Syndromic and non-syndromic diseases
Syndromic associated diseases (4)
– Cleidocranial dysplasia
– Gardner’s syndrome
– Trichorhino phalangic syndrome
– Cleft Lip and palate
Mutations in — gene identified as causal
RUNX2
RUNX2 is a master regulator of
osteoblastogenesis and bone formation
Characterized by (3)
delayed closure of the sutures, aplastic or hypoplastic
clavicle formation, short stature and dental abnormalities
Most common human developmental
craniofacial anomaly
tooth angiogenesis
Hypodontia
Missing one to five teeth (excluding 3rd
molars)
Oligodontia
Missing six or more teeth (excluding 3rd
molars)
Anodontia (2)
• Missing all teeth
• Most severe and rare form - mostly
syndromic
Hypodontia (excluding 3rd molars) prevalence rate of tooth angenesis (2)
- Worldwide – 6.4%
* Ranging from 4.4% (Caribbean) to 13.4% (Africa)
Third molars prevalence rate of tooth angenesis
Worldwide – 22.6% (5.3 – 56.0%)
Primary (deciduous) prevalence rate of tooth angenesis
Rare - 0.1 – 2.4%
Presentation
• Syndromic association1
• Over 60 different conditions listed in OMIM
• Isolated, non-syndromic trait
• Most common presentation
• Mandibular 2nd premolar (3%), maxillary lateral incisor
(1.7%), maxillary 2nd premolar (1.5%), and mandibular
central incisor (0.3%)
• Associated phenotypes:
• Conical crown shape, molar taurodontism, enamel
hypoplasia, transposition, canine misposition, etc.
two of the most commonly mutated genes in tooth angiogenesis
• MSX1 and PAX9
on site subjects (4)
Received genetic variant lists of subjects following whole exome sequencing
Identified common variant(s) among variant lists of subjects with tooth agenesis
Excluded common variant(s) present in variant list of subject without tooth
agenesis
Candidate variant(s)
Segregation of mutation in affected members of
—
kindred
Variant Analysis: (3)
DOMINO, CADD, and pLI
Literature based search to assess (2) of identified mutation
potential function
and/or consequences
candidate variant identification results (4)
Whole Exome Sequencing of four on-site subjects
26 heterozygous variants segregated correctly with the tooth agenesis phenotype
Likelihood of autosomal dominant inheritance
evaluated by DOMINO
7 candidate variants identified
how many candidate variant analysis genes identified
7
RNF43 family
RING finger E3 ubiquitin ligase family
RNF43 mechanism of action
Tumor suppressor that exerts a negative feedback mechanism in the Wnt/β-catenin signaling pathway
Ubiquitinates Frizzled family of Wnt receptors for —
degradation
Consequently downregulated — signaling
Wnt
R-spondin family and receptors (Lgr4-6) involved in development of — teeth
murine
Lgr/R-spondin complex has been shown to inactivate Rnf43 in intestinal epithelial crypt stem cells leading to enhancement of
Wnt signaling
DKK1 is also a
Wnt signaling inhibitor
Known to be associated with tooth agenesis when —
overexpressed
AXIN2 mutation
impairs Wnt/b-catenin signaling in human results in tooth agenesis and colorectal cancer.
major proteins of enamel (5)
amelogenin ameloblastin enamelin kalikrin 4 mmp-20
Amelogenin
Stabilizes the amorphous Ca-P phase, control of apatite crystal
morphology and organization, control of enamel thickness.
Amelogenins have the ability to self-assemble into nanosperes and
thereby guide HAP crystal formation/growth.
Ameloblastin
Cell adhesion protein, controls cell differentiation, maintains rod
integrity
Enamelin
Cooperates with amelogenin to control mineral nucleation and
elongated growth
Kallikrin 4
Digests enamel proteins during maturation stage facilitating their
removal and hardening the final layer of enamel
Mmp-20
Cleaves amelogenin, ameloblastin and enamelin at the secretory stage
to produce stable intermediates with defined functions.
Amelogenesis imperfecta
disorder of tooth development. This condition causes teeth
to be unusually small, discolored, pitted or grooved, and prone to rapid wear and
breakage. Other dental abnormalities are also possible. These defects, which vary among
affected individuals, can affect both primary (baby) teeth and permanent teeth
Amelogenin:
im protein in
x-linked to
forming enamel
amelogenesis imperfecta
Enamelin:
~186kDa protein and ~5% of the enamel matrix.
major dentin extracellular matrix molecules (7)
type 1 collagen SIBLING family proteins DSPP DMP1 bone sialoprotein osteopontin MEPE
major component found in dentin
type 1 collagen (90%)
SIBLING family proteins
small integral binding ligand N linked glycoproteins
Dentin Sialophosphoproteins
DSPP
Immediately cleaved after secretion into DSP,
DGP and DPP
Dentin Matrix Protein 1 (DMP1)
Produced by odontoblasts and early-stage
osteocytes
Bone Sialoprotein
Role in biomineralization
Osteopontin
HA binding and contains an RGD motif,
mineralization inhibitor
MEPE
Matrix Extracellular Phosphogylcoprotein,
contains an RDG motif and in bone appears to be
an inhibitor of mineralization
Dentinogenesis imperfecta:
Dentinogenesis imperfecta is a disorder of tooth development. This condition causes the teeth to be discolored (most
often a blue-gray or yellow-brown color) and translucent. Teeth are also weaker than normal, making them prone to
rapid wear, breakage, and loss.
These problems can affect both primary (baby) teeth and permanent teeth. Researchers have described three types
of dentinogenesis imperfecta with often subtle differences in dental abnormalities.
Dentinogenesis imperfecta: type 1
occurs in people who have osteogenesis imperfecta, a genetic condition in which bones are brittle and easily
broken. The primary teeth tend to be more severely affected than the permanent teeth.
Dentinogenesis imperfecta: type 2 and 3
usually occur in people without other inherited disorders. In Type II both dentitions are equally
affected. In Type III the dentin is extremely thin and the pulp chamber is extremely enlarged. The teeth in Type III are
often referred to as “shell teeth”.
Type I collagen genes (COL1A1 or COL1A2) associated with
osteogenesis imperfecta (OI) (DGI-I)
Dentinogenesis imperfecta type I occurs as part of osteogenesis imperfecta, which is
caused by mutations in
one of several other genes (most often the COL1A1 or COL1A2
genes).
A deficiency of dentin sialophosphoprotein (DSPP) had been suggested as a causative
factor in
dentinogenesis imperfecta (Takagi & Sasaki 1998)
Dentin dysplasis (DD)
Milder dentin defects than DI-II&III
Mutation (Y6D) in a signal peptide of DSPP (Dentin Sialophosphoprotein),
resulting in the reduction of the amount of
secreted DSPP protein into dentin matrix
Gene mutations can be broadly classified into two categories,
gain-of-function mutations and loss-of-function mutations
Affected children resulting from consanguinity in a family is an indicator of a
recessive trait disease
Genetic diseases of the — — and dentition are collectively the most common of the genetic disorders
craniofacial skeleton
— diseases of the dentition occur in combination with other diseases, while — diseases do not
Syndromic
non-syndromic
Tooth number genetic disorders result from a wide variety of
genetic mutations
Importantly mutations in many of the genes affecting tooth number/formation can be an early predictor of
potential future diseases such as cancer
Most of the amelogenesis imperfecta is caused by mutations in (6)
amelogenin, ameloblastin, enamelin, amelotin, enamelysin (MMP-20), and kalliklein4
Dentinogenesis imperfecta is caused by mutations in
type I collagen associated with osteogenesis imperfecta and in DSPP
