Lecture 2 - Molecular Genetics of Craniofacial Disorders

Question 1

Most Common Features of CranioFacial Malformation

Answer 1

Abnormal Development,
Problems with closure of sutures,
and Clefting

Question 2

What is the most common type of birth defect

Answer 2

Craniofacial Malformation

Question 3

What are the genetic modes disorders can take

Answer 3

Multigenic, Polygenic, Complex - from an accumulation of mutations (CL/P)
Multigenic with environemntal factors, multifactorial (CL/P)
Genetic Heterogeneity - mutations in more than one gene can cause same phenotype (Crouzon)
Allelic - different mutations in same gene can cause different disorders (FGFR2, FGFR3)
Same mutation in Same gene can cause different - Due to modifier (FGFR; Craniosynostosis forms in Crouzon or in pfeiffer)
Monogenic - one gene mutation can cause a disorder

Question 4

Oral Clefts Types

Answer 4

Type: Multigenic mostly, or it can be multigenic with environmental factors
Cleft lip - unilateral, or bilateral
Cleft Palate - incomplete fusion of palatal process

Question 5

Oral Cleft Causes (three types)

Answer 5

Mechanical - small oral cavity large tongue, prevents elevation of palatal shelf
Environmental Factors - Alcohol, Cig, Medication, Retinoic Acid, insufficient blood supply during development
Multigenic - most cases are multigenic,
Differing incidence in racial groups
Risk with affected parent 10%
Risk with affected grandparent 2%

Question 6

Polymorphisms found through GWAS studies (discussed in lecture, there are others from the IPS)

Answer 6

MSX1 - premature stop codon causing problem with BMP

IRF6 - Cleft in Van Der Woude syndrome

Question 7

Craniosynostosis (Cause and affect)

Answer 7

over 100 syndromes involve this, many of them are autosomal dominant. Caused by Premature closure of one or more calvarial sutures, leading to abnromal skull and faceial shape, and pressure

Question 8

Craniosynostosis Boston Type (Cause and phenotype)

Answer 8

Different mutations in the same gene can cause different disorders.
Mutation in the homeodomain of the homeobox for gene Msx2
Phenotype - frontal bossing, clover leaf skull, and short first metatarsals

Question 9

Importance of FGFR2

Answer 9

Fibroblast Growth Factor 2 Receptor is a hotspot for mutations.
It has extracellular domain, transmembrane, and intracellular tyorisine kinase
most mutations exist in Exon 7 and 9.
These result in Craniosynostosis diseases (different mutations same gene)

Question 10

Mutations associated with Mutations in FGFR2

Answer 10

Pfieffer, Apert, Crouzon, Jackon Weiss
The mutations are gain of function and affect ligand binding in extracellular domain.
Mutation in transmembrane gets beare-stevenson syndrome (which has cutis gyrata)

Question 11

Same Mutation in same gene different phenotype Example

Answer 11

Cys342Tyr, and Cys342Arg Mutations in the extracellular domain of FGFR2 have been found in both pfeiffer or crouzon
so this indicates modifier genes play an important role in patheogenesis
These frequency of mutations coorelated to advanced paternal age

Question 12

Gene Mutations causing tooth agenesis

Answer 12

Hypodontia - Mutations in MSX1, or ablation (inhibition) of DLX1 or DLX2 in mice
OligoDontia - another MSX1 mutation and patients with witkop syndrom
Anondontia - pax9 ablation or EDA prbolems,
Supernumery - found with CCD

Question 13

Osteosclerosis

Answer 13

Increased bone density

Question 14

Hyperostosis

Answer 14

increased cortical bone thickening

Question 15

CMD vs Cherubism

Answer 15

have imbalance with bone homestasis
CMD - has increase bone deposition
CBM (Cherubism) is increase in bone resoprtion

Question 16

Craniometaphyseal Dysplasia (CMD) (Genetics and Clincal Features)

Answer 16

Genetics -AS dominant, (sometimes recessive) sporadic and incidence is rare, but has 100% incidence
Phenotype - increased bone density,
closure of foramina,
neuronal compression.
Widening of bone at the ends, (erlenmeyer flask shape)
CMD patients present with facial deformaties like nose bossing and wide nasal bridge
have breathing and feeding problems
blindness hearing loss and palsy
Frequently teeth dont erupt

Question 17

ANKH Mutation

Answer 17

causes autosomal dominant CMD - it is a trasnmembrane protein for Pyrophosphate transport

Question 18

Cherubism (CBM) (genetics and phenotype)

Answer 18

Genetics - AS dominant, rare, variable expression
Phenotype
- age onset is later (coincides with tooth bone resorption with tooth eruption)
- regresses after puberty
bone resportion is replaced with fibrous tissue so there is alike a tumor
- leads to cyst like moltilocular radiolucencies visible in x ray
- tumor consists of mass of osteoblastic stromal cells and clusters of multinucleatesd osteoclastic cells (so more ocsteoclastic stuff)
- submandibular lumph node enlargement (visible)
- problem with tooth eruption, malocclusion, and malpositioned teeth. can have tooth agenesis, and root resorption

Question 19

what mutation causes Cherubism

Answer 19

SH3BP2, which is a signaling molecule and regulates the signal pathway. This mutation form cannot be degaded
molecule made becomes zip code to nucleus so its just like going

Question 20

how to study genetic disorder

Answer 20

Determine Trait is monogenic or multi
pedigree or association study
gene mapping or GWS
Find Gene locus - with linkage analysis
positional cloining, or find a similar gene in rat 
mutation detection and verificaiton 
or functional tests

Question 21

How to verify a mutation

Answer 21

Test for cosegregation of mutation with disease phenotype
Test a large number of controls for this sequence variance
Show impoact of mutaiton on protein pathway
recreate phenotype in culture
recreate phenotype in mouse model