How Do Mutations Affect Health and Tooth Development

Question 1

continuum of diseases

Answer 1

environmental to genetic

Question 2

The new HGMD professional release becomes available with a total of 170,118 — —

Answer 2

mutation entries

Question 3

Loss-of-function mutation

Answer 3

Absence results in dysfunction

Question 4

what do loss of function mutations result in?

Answer 4

less or no function of certain proteins

Question 5

loss of function mutations constitute many — — cases in enzyme deficiency

Answer 5

autosomal recessive

Question 6

two subtypes of loss of function

Answer 6

halpoinsuffciency

dominant negative

Question 7

haploinsufficiency

Answer 7

reduced gene dosage is not sufficient to permit the cell to function properly

Question 8

example of haploinsufficiency

Answer 8

Marfan syndrome with fibrillar mutation

Question 9

dominant negative

Answer 9

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

Question 10

In cases of polymeric molecules, such as collagen, dominant negative
mutations are often more

Answer 10

deleterious than mutations causing the production of

no gene product (cancer)

Question 11

example of dominant negative

Answer 11

osteogenesis imperfecta

Question 12

with dominant negative, the mutant protein is happy, but

Answer 12

annoying and disturbing other good protein function

Question 13

Gain-of-function mutation

Answer 13

Increased function results in dysfunction

Question 14

with gain of function mutations, mutations in certain genes gain a

Answer 14

new and abnormal function of the protein

Question 15

example of gain of function mutation (2)

Answer 15

Charcot-Marie-Tooth sensory neuropathy, Cherubism

Question 16

Over 300 genes identified that have

mutations associated with (3)

Answer 16

tooth patterning,

morphogenesis defects and cell differentiation defects

Question 17

As a collective group craniofacial genetic

diseases are the

Answer 17

most common, 1/3 of diseases involve the craniofacial region

Question 18

Double Bar indicates

Answer 18

consanguineous mating

Question 19

— — diseases often present in

consanguineous marriages

Answer 19

Autosomal recessive

Question 20

—- 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

Answer 20

Consanguinity

Question 21

The developmental signaling pathways that drive

tooth development are also critical in the

Answer 21

development of many other organs

Question 22

Tooth developmental defects should perhaps be

thought of as a

Answer 22

potential risk factor for other

diseases that manifest later in life

Question 23

genetic diseases and the dentition (6)

Answer 23

malocclusion syndromes 
craniofacial malformations
bone mass traits 
tooth genesis 
tooth movement 
tooth development disorders

Question 24

malocclusion syndromes (3)

Answer 24

– Pierre-Robin
– Treacher Collins
– Marfan syndrome

Question 25

Craniofacial malformations (4)

Answer 25

– Crouson – Apert – Pfeiffer – Clefting syndromes (lip and palate)

Question 26

Bone Mass Traits (3)

Answer 26

– Sclerosteosis and van Buschem’s – High Bone Mass and OPPG – Paget’s Disease

Question 27

Tooth Development Disorders (2)

Answer 27

– Dentinogenesis Imperfecta | – Amelogenesis Imperfecta

Question 28

symptoms of ectodermal dysplasia

Answer 28

* 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

Question 29

- -- --- is fairly common, but | - -- --- --- is rare

Answer 29

Tooth impaction | multiple impacted teeth

Question 30

supernumerary teeth (2)

Answer 30

Syndromic and non-syndromic diseases

Question 31

Syndromic associated diseases (4)

Answer 31

– Cleidocranial dysplasia – Gardner’s syndrome – Trichorhino phalangic syndrome – Cleft Lip and palate

Question 32

Mutations in --- gene identified as causal

Answer 32

RUNX2

Question 33

RUNX2 is a master regulator of

Answer 33

osteoblastogenesis and bone formation

Question 34

Characterized by (3)

Answer 34

delayed closure of the sutures, aplastic or hypoplastic | clavicle formation, short stature and dental abnormalities

Question 35

Most common human developmental | craniofacial anomaly

Answer 35

tooth angiogenesis

Question 36

Hypodontia

Answer 36

Missing one to five teeth (excluding 3rd | molars)

Question 37

Oligodontia

Answer 37

Missing six or more teeth (excluding 3rd | molars)

Question 38

Anodontia (2)

Answer 38

• Missing all teeth • Most severe and rare form - mostly syndromic

Question 39

Hypodontia (excluding 3rd molars) prevalence rate of tooth angenesis (2)

Answer 39

* Worldwide – 6.4% | * Ranging from 4.4% (Caribbean) to 13.4% (Africa)

Question 40

Third molars prevalence rate of tooth angenesis

Answer 40

Worldwide – 22.6% (5.3 – 56.0%)

Question 41

Primary (deciduous) prevalence rate of tooth angenesis

Answer 41

Rare - 0.1 – 2.4%

Question 42

Presentation

Answer 42

• 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.

Question 43

two of the most commonly mutated genes in tooth angiogenesis

Answer 43

• MSX1 and PAX9

Question 44

on site subjects (4)

Answer 44

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)

Question 45

Segregation of mutation in affected members of | ---

Answer 45

kindred

Question 46

Variant Analysis: (3)

Answer 46

DOMINO, CADD, and pLI

Question 47

Literature based search to assess (2) of identified mutation

Answer 47

potential function | and/or consequences

Question 48

candidate variant identification results (4)

Answer 48

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

Question 49

how many candidate variant analysis genes identified

Answer 49

7

Question 50

RNF43 family

Answer 50

RING finger E3 ubiquitin ligase family

Question 51

RNF43 mechanism of action

Answer 51

Tumor suppressor that exerts a negative feedback mechanism in the Wnt/β-catenin signaling pathway

Question 52

Ubiquitinates Frizzled family of Wnt receptors for ---

Answer 52

degradation

Question 53

Consequently downregulated --- signaling

Answer 53

Wnt

Question 54

R-spondin family and receptors (Lgr4-6) involved in development of --- teeth

Answer 54

murine

Question 55

Lgr/R-spondin complex has been shown to inactivate Rnf43 in intestinal epithelial crypt stem cells leading to enhancement of

Answer 55

Wnt signaling

Question 56

DKK1 is also a

Answer 56

Wnt signaling inhibitor

Question 57

Known to be associated with tooth agenesis when ---

Answer 57

overexpressed

Question 58

AXIN2 mutation

Answer 58

impairs Wnt/b-catenin signaling in human results in tooth agenesis and colorectal cancer.

Question 59

major proteins of enamel (5)

Answer 59

``` amelogenin ameloblastin enamelin kalikrin 4 mmp-20 ```

Question 60

Amelogenin

Answer 60

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.

Question 61

Ameloblastin

Answer 61

Cell adhesion protein, controls cell differentiation, maintains rod integrity

Question 62

Enamelin

Answer 62

Cooperates with amelogenin to control mineral nucleation and elongated growth

Question 63

Kallikrin 4

Answer 63

Digests enamel proteins during maturation stage facilitating their removal and hardening the final layer of enamel

Question 64

Mmp-20

Answer 64

Cleaves amelogenin, ameloblastin and enamelin at the secretory stage to produce stable intermediates with defined functions.

Question 65

Amelogenesis imperfecta

Answer 65

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

Question 66

Amelogenin: im protein in x-linked to

Answer 66

forming enamel | amelogenesis imperfecta

Question 67

Enamelin:

Answer 67

~186kDa protein and ~5% of the enamel matrix.

Question 68

major dentin extracellular matrix molecules (7)

Answer 68

``` type 1 collagen SIBLING family proteins DSPP DMP1 bone sialoprotein osteopontin MEPE ```

Question 69

major component found in dentin

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type 1 collagen (90%)

Question 70

SIBLING family proteins

Answer 70

small integral binding ligand N linked glycoproteins

Question 71

Dentin Sialophosphoproteins | DSPP

Answer 71

Immediately cleaved after secretion into DSP, | DGP and DPP

Question 72

Dentin Matrix Protein 1 (DMP1)

Answer 72

Produced by odontoblasts and early-stage | osteocytes

Question 73

Bone Sialoprotein

Answer 73

Role in biomineralization

Question 74

Osteopontin

Answer 74

HA binding and contains an RGD motif, | mineralization inhibitor

Question 75

MEPE

Answer 75

Matrix Extracellular Phosphogylcoprotein, contains an RDG motif and in bone appears to be an inhibitor of mineralization

Question 76

Dentinogenesis imperfecta:

Answer 76

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.

Question 77

Dentinogenesis imperfecta: type 1

Answer 77

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.

Question 78

Dentinogenesis imperfecta: type 2 and 3

Answer 78

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”.

Question 79

Type I collagen genes (COL1A1 or COL1A2) associated with

Answer 79

osteogenesis imperfecta (OI) (DGI-I)

Question 80

Dentinogenesis imperfecta type I occurs as part of osteogenesis imperfecta, which is caused by mutations in

Answer 80

one of several other genes (most often the COL1A1 or COL1A2 genes).

Question 81

A deficiency of dentin sialophosphoprotein (DSPP) had been suggested as a causative factor in

Answer 81

dentinogenesis imperfecta (Takagi & Sasaki 1998)

Question 82

Dentin dysplasis (DD)

Answer 82

Milder dentin defects than DI-II&III

Question 83

Mutation (Y6D) in a signal peptide of DSPP (Dentin Sialophosphoprotein), resulting in the reduction of the amount of

Answer 83

secreted DSPP protein into dentin matrix

Question 84

Gene mutations can be broadly classified into two categories,

Answer 84

gain-of-function mutations and loss-of-function mutations

Question 85

Affected children resulting from consanguinity in a family is an indicator of a

Answer 85

recessive trait disease

Question 86

Genetic diseases of the --- --- and dentition are collectively the most common of the genetic disorders

Answer 86

craniofacial skeleton

Question 87

--- diseases of the dentition occur in combination with other diseases, while --- diseases do not

Answer 87

Syndromic | non-syndromic

Question 88

Tooth number genetic disorders result from a wide variety of

Answer 88

genetic mutations

Question 89

Importantly mutations in many of the genes affecting tooth number/formation can be an early predictor of

Answer 89

potential future diseases such as cancer

Question 90

Most of the amelogenesis imperfecta is caused by mutations in (6)

Answer 90

amelogenin, ameloblastin, enamelin, amelotin, enamelysin (MMP-20), and kalliklein4

Question 91

Dentinogenesis imperfecta is caused by mutations in

Answer 91

type I collagen associated with osteogenesis imperfecta and in DSPP