Lecture 35 How do mutations affect health and tooth development Flashcards
1
Q
What are environmental diseases?
A
- influenza
- measles
- infections
2
Q
What are in the middle of the disease continuum?
A
- diabetes
- CV diseases
- Osteoporosis
3
Q
What would be 2 genetic diseases?
A
- cystic fibrosis
- hemophilia A
4
Q
Mutation data base total number
A
- 120,000 (large numbers)
5
Q
What are the broadest classes of protein functions resulting form gene mutations?
A
- loss-of-function mutation
- gain of function mutation
6
Q
What is a loss of function mutation?
A
- absence results in dysfunction
- mutations results in less or no function of certain proteins
- many autosomal recessive cases in enzyme deficiency
7
Q
Haploinsufficiency
A
- reduced gene dosage is not sufficient to permit the cell to function properly
- Marfan syndrome with fibrillin mutation
- only half of alleles working (50 % of protein being made)
8
Q
Dominant negative mutations
A
- a mutation whose product adversely affects the normal product
- osteogensis imperfect
- disrupts good proteins function
9
Q
Gain of function mutation
A
- increased function results in dysfunction
- mutations in certain genes gain a new and abnormal function of protein
- dense skeleton
10
Q
What is the most common type of disease?
A
- craniofacial genetic disorders
11
Q
What indicated consanguineous mating?
A
- double bar
related individuals
12
Q
High bone mass kindred
A
- autosomal dominant trait
- (male to female)
- (female to male)
- each level effected
13
Q
What would be an appropriate name for bone diseases?
A
- cranio tubular hyperostosis
14
Q
What are present in consanguineous marriages?
A
- autosomal recessive diseases
15
Q
Why are autosomal recessive diseases frequently found in the mediterranean?
A
- because they allow first cousin marriages
16
Q
Why do genetic diseases relate to teeth?
A
- the developmental signaling pathways that drive tooth development are critical in the development of many other organs
- tooth development should perhaps be thought of as a potential risk factor for other diseases that manifest later in life.
17
Q
What are the malocclusion syndromes?
A
- pierre robin
- treacher collins
- marfan syndrome
18
Q
What are the craniofacial malformations?
A
- crouson
- apert
- pfeiffer
- clefting syndromes (lip and palate)
19
Q
What are the bone mass traits?
A
- sclerosteosis and van buschem’s
- high bone mass and OPPG
- Paget’s Disease
- tooth agenesis
- tooth movement
= tooth development disorders
20
Q
Schlerosteos and van buschems
A
- mutations in sosh gene
21
Q
High bone mass and OPPG
A
- LRP5
22
Q
Tooth agenisis
A
- patient missing teeth
23
Q
Pagents disease
A
- increases bone mass
24
Q
Ectodermal dysplasia symptoms
A
- abmoral nails, teeth, absent or think hair, absent tears, decreased skin color etc
25
Supernumarry teeth
- tooth impaction is fairly common but umtiple impacted teeth is rare
26
What is a syndromic disease?
- when another disease effects the tooth development
27
Syndromic associated diseases:
- Cleidocranal dysplasia
- Gardners syndrome
- Trichorhino phalangic syndrome
- Cleft lip and palate
28
Non-syndromic
- no comorbities
29
Why is RUNX2 important?
- it is a master regulator of osteoblastogenis and bone formation
-
30
Cleidocrania dysplasia
- mutation in RUNX 2 gene
- cahracterized by delayed closer of the sutures, aplastic or hypoplastic clavicle formation, short stature and dental abnormalities
31
What is axin2 significant in?
-and AXIN2 mutation impairs the Wnt/b-catenin signaling and results in tooth agenesis and colorectal cancer
32
What does an axin2 mutation result in?
- tooth agenesis
| - colorectal cancer
33
What is keratin 17 responsible for?
- oligodontia
| - (facial cysts and other comorbities associated with keratin 17)
34
what is LRP6 associated with?
- autosomal dominant oligodontia
| identified by exome sequencing
35
What is amelogeninesis imperfecta?
- a disorder of tooth development
- this disorder causes teeth to be unusually small, discolored. pitted or grooved and prone to rapid wear and breakage. O
36
Does amelogenin occur in primary or permanent teeth?
- both
37
What is the main protein important in forming enamel?
- amelogenin
38
When you see an X on the mutation chart what does it mean?
- truncated/ termination
39
What happens to mouse when given amelx knockout?
- incisors wear quickly
- sclaped
- no enamel
40
Ameloblastin
another protein that is present in enamel
| - deletion of ameloblastin exon 6 is associated with amelogeneissi imperfecta
41
What proetein makes up 10% of enamel matrix?
- ameloblastin
| 70kDa protein
42
What protein makes up 5% of enamel matrix?
- enamelin
| 186kDa protein
43
What protein has a splice 7 insertion?
- enamelin
44
Amelotin
- a potential canidate gene for amelogenesis imperfecta
- more recently studied
- present in knockout mice
45
What happens when there is deletion of amelotin exons 3-6 ?
- amelogenesis imperfecta
46
What is WRD72?
- a new gene responsible for amelogenesis imperfecta with less functional information
47
What is WRD72's function?
- regulator of enamel formation
| - without this gene enamel doesn't mineralize properly
48
What is the gene that is important for hydorxyapatite crytsal formation?
- C4orf26
49
What is enamelysin (MMP20)?
- a metalloproteinase that degrades amelogenin
| - if you dont remove amelogenin itll be less dense and wears easily
50
Mutations to these genes affect enamel development and give rise to amelogenisis imperfecta?
- amelogenin
- ameloblastin
- enamelin
- amelotin
- WRD72
- C4orf26
- Enamelysin (MMP20)
- kalliklein
51
What is kalliklien?
- serine protease which digest enamel matrix
52
What is the major component found in dentin?
- type 1 collagen
53
What is dentinogenesis imperfecta?
- a disorder of tooth development
54
What is a symptom of dentinogenesis imperfecta?
- teeth are discolored (blue-gray or yellow brown) and translucent
- weaker than normal
- prone to rapid wear, breakage, and loss
55
Does dentinogenesis only occur in deciduous teeth?
- no it occurs in primary teeth as well
56
What is type 1 dentinogenesis imperfecta?
- type 1 occurs in people who have osteogenesis imperfecta, a genetic condirion in which bones are brittle and easily broken
- the primary teeth tend to be more severly affected than the permanent teeth
57
What is type II and III dentinogensis imperfecta?
- usually occurs in people without inherited disorders
| - In type II both dentitions are equally affected
58
What is a characteristic of type III dentinogenesis imperfecta?
- the dentin is extremely thin and the pulp chamber is extremely enlarged
- the teeth in type III are often reffered to as shell teeth
59
Shell teeth are found in?
individuals with type III dentinogenesis imperfecta
60
T/F type I collagen genes are associated with osteogenesis imperfecta
True
61
What disorder occurs as part of osteogenesis imperfecta?
- Type I dentinogenesis imperfecta
| - caused by mutations inn one of several other genes (most often the COL1A`1 or COL1A2)
62
What has been suggested as a causative factor in dentinogenesis imperfecta?
- A deficiency of dentin sialophosphoprotein (DSPP)
| - Type II or III
63
What is more severe effects DI-DIII or DD?
- DI-III
64
Dentin dysplasis results when?
- there is a mutation (Y6D) in a signal peptide of DSPP resulting in the reduction of the amount of secreted DSPP protein into dentin matrix
65
What is a strong indicator of a recessive trait?
- affected children resulting from a consanguinity family
66
What is the most common genetic disorders?
- craniofacial skeleton and dentition disorders
67
What is the function of 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
68
What is the function of ameloblastin?
- cell adhesion protein, controls cell differentiation, maintains rod integrity, forms dentin
69
What is the function of enamelin?
- cooperates with amelogenin to control mineral nucleation and elongated growth
70
What is the function of kallikrin 4?
- digests enamel proteins during maturation stage facilitating their removal and hardening the final layer of enamel
71
What is the function of mmp-20?
- cleaves amelogenin , ameloblastin, and enamelin at the secretory stage to produce stable intermediates with defined functions
