564 Molecular Genetic Development

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Hirschsprung Syndrome: Gene & gene product function

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RET gene,
Ret protein is the GDNF receptor, needed for migration & differentiation of Neural Crest Cells into Enteric neurons

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Neurocristopathy

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abnormalities of neural crest derived tissues

Hirschsprung Syndrome

Lance: make sure that we know all of the Neurocristopathies!!

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5 facts about Hirschsprung syndrome

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1. Neurocristopathy --> disorder of enteric nervous system

2. absence of ganglion cells is the reason for insufficient peristalsis in the lower digestive tract

3. RET gene is essential for the migration and differentiation of NCCs into enteric neurons

4. distended transition zone segment seen in radiograph

5. Definitive diagnosis based on absence of absence of ganglion cells & hypertrophied nerve trunks

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Meconium

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newborn feces

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Hypertelorism

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widely spaced eyes

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o Exophthalmos

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eyes protrude (pushed out) = bug eyed

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o Strabismus

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can’t focus both eyes to the same point in space

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o Acanthosis Nigricans

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hyperpigmentation of skin folds- pits & neck

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Apert-Crouzon Syndrome: gene & molecular mech

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FGFR mut --> constitutively active causing increased proliferation & differentiation --> ossification of cranial sutures

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Chronic Myelogenous Leukemia: Molecular Mech

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translocation between chs 9 and 22
--> o Bcr-Abl
Bcr has GAP & dimerization domain
Abl is Tyr kinase
Fusion --> generates a dimer of constitutively active tyrosine kinase activity
=>oncogene--> increased proliferation & decreased apoptosis

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- Blast Crisis

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Chronic Myelogenous Leukemia

over 20% of the blood cells are blast cells
rapid proliferation
limited response to drugs.
--> deadly bleeding, infections, or overwhelming release of cytokines in a form of systemic shock vaguely described "blast crisis".

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o Gleevec

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binds Abl & inhibits it’s tyrosine kinase activity

1st cancer specific drug

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- Syndrome

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group of symptoms that characterize a disease, psychological disorder, or other abnormal condition

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What is the leading cause of Deaf-Blindness

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Usher Syndrome

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o Retinitis Pigmentosa

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disruption in photoreceptor cells leading to slow degeneration of retinal layer

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What happens in the eye in Usher Syndrome

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Thinning of ONL & OPL

Thickening of INL

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Usher Syndrome: Molecular Mech

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Locus Heterogeneity (Multi genes @ same time)
Mutation in MYO7A (Myosin 7a)

--> Inner Ear => destabilize ultra-structure of stereocilia preventing activation of mech gated ion channels

Retina --> MYO7A is in adherens junctions --> disruption of RPE, thining of ONL & OPL, and thickening of INL

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types of Usher Syndrome

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1 - Born deaf/balance problems & go blind w/in 10 years

2. poor hearing & go blind w/in 20 years

3. variable deafness & blindness is progressive

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Interactome

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complex series of molecular interactions which determines phenotypic severity

In Usher Syndrome the Interactome is how several mutations across the genome lead to the syndrome

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Diagnosis of Usher syndrome

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complete gene sequencing

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Familial Adenomotous Polyposis Coli: Phenotypes

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ACE is a BAD DOG
o Adenomatous Polyps:
o Congenital Hypertropy of RPE
o Extracolonic Cancers

o Benign Cutaneous Lesions
o Adrenal Masses
o Dental Abnormalities:

o Desmoid Tumors:
o Osteomas:
o Gastric Polyps

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Usher Syndrome inheritance

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Autosomal recessive

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Familial Adenomotous Polyposis Coli: Diagnosis

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100+ Colorectal Adenomotous polyps b/f 40

or less than 100 + relative

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Familial Adenomotous Polyposis Coli: Molecular Mech

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APC gene (APC protein is a Tumor Suppressor) whose job is to help Ub Beta-Catenin w/out Wnt signaling

Mutation --> unregulated proliferation

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neurofibroma

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benign nerve sheath tumor

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Neurofibromatosis 1: Molecular Mech

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NF1 gene is a tumor suppressor, down regulates Ras (GAP) & up regulates cAMP (stabilizing AC, cAMP is needed for PKA to inhibit growth)

Mutation in NF1 causes it to not down regulte Ras --> cell growth & proliferation

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Neurofibromatosis 1: Diagnosis

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need 2 of the following
o Café Au Lait spots: >6 & > .5cm pigmented birthmarks
o Intertriginous Freckling:
o 2 or more Lisch Nodules
o 2 or more Neurofibromas or one plexiform neurofibroma
o Optic Gliomas
o Skeletal Abnormalities
o 1st degree relative w/NF1

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plexiform neurofibroma

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Solitary nerve sheath tumor

nerve facial tumor

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Café Au Lait spots

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pigmented birthmarks

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Intertriginous

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Intertriginous : an area where two skin areas may touch or rub together.

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Lisch Nodules

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nodule of the iris

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Optic Pathway Gliomas

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growth that puts pressure on Optic nerve causing Proptosis, vision loss, & precocious puberty

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Proptosis

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= Exophthalmos
eye bulges out

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Electroporation

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technique that uses an e- field to make short lived holes in PM to introduce shit into cells

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facts about Neurofibromatosis 1

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1. Mut/Del causing neural crest tumors

2. NF1 gene codes Neurofibromin

3. Neurofibromin is a GAP for Ras, down regulating cell growth & proliferation

4. diagnosis can be made w/ 2 or more Lisch Nodules & Optic Gliomas

5. NF1 mutation may overactivate Ras

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- Metastatic

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capable of spreading to distant tissues

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- Malignant

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invasive local tissue
less differntiated, atypical structure

Erratic Growth

may be metastatic

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Oncogenes

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 Control cell growth, survival, apoptosis
 Gain of function mutation
 Have dominant effect
Activation
Point mutation
Amplification of gene expression (genetic or epigenetic)
Chromosomal translocation

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Tumor suppressor genes

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Gatekeepers & Caretakers
Loss of function mutation
 Need loss of function of both alleles to become malignant
 Two hit hypothesis

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Lance:

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if we have time read cancer handout

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- Leukocoria

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white pupil reflex, “cat’s eye” reflex

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• Exotropia

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Eye turning out toward ear

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• Esotropia

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Eye turning in toward nose

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2 Hit hypothesis

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Tumor Suppressor gene needs to have loss of function in both alleles

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Retinoblastoma: Molecular Mech

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Rb protein is a tumor suppressor gene (need 2 loss of functions)
- is a checkpoint btw G1 & S
- exit from cell cycle for retinal progenitor cells

Mutation leads to

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Crohn: what is it?

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Inflammatory Bowel Disease - from mouth to anus

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ileocolitis

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inflammation of the mucous membrane of the ileum and colon

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Infliximab (Remicade)

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blocks TNF-alpha

approved for Crohn

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Crohn: Molecular Mech

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NOD2- - encodes leucine-rich repeat binds MDP of peptidylglycan in Bac
- activating NF-KappaB --> immune and inflammatory response

Mutation in NOD2 then don't fight off pathogenic Bac --> infection & disease

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X-linked Severe Combined Immune Deficiency: gene

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IL2GR- common receptor in Immune cells, codes for gamma chain

Key component in the maturation of lymphocytes

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X-linked Severe Combined Immune Deficiency: molecular mech

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Mutation in IL2GR causes decreased maturation of lymphocytes

T(-) B(+) NK(-)

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- Echolalia

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repeating words

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- Coprolalia

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involuntary swearing

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Tourette: gene

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SLITRK1: involved in neurite outgrowth

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Yeast 2 hybrid Assay

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ID protein-protein interactions

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- Erythematosus

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red skin caused by dilatation and congestion of the capillaries

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SLE: symptoms

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SOAP BRAIN MD

Serositis
Oral ulcers
Arthritis
Photosensitivity

Blood
Renal disorder:
Anti nuclear Ab
Immunologic disorder
Neurologic disorder

Malar rash
Discoid rash

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Discoid rash

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disc shaped rash on areas exposed to sunlight

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Lupus gene

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IRF5: TF that regulates Type I INF response gene

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Basics of SLE

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chronic inflammatory autoimmune disease

Complex genetic, environment & immuno invovling many key genes (Polygenic inheritance)
more common in females

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Charcot Marie Tooth: how does it happen

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Unequal crossing over btw 2 homologous repeats on 17p12 can result in either
a. 3 copies of PMP22 gene
b. 1 copy of PMP22 gene w/HNPP phenotype

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areflexia

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Absence of neurologic reflexes such as the knee jerk reaction.

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Charcot Marie Tooth: Molecular Mech

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unequal crossing over btw homologous repeats on 17p12 --> 3 copies of PMP22

PMP22 gene
- Duplication in chromosome 17p12 leads to abnormal myelin protein structure & function
- Demyelination of peripheral nerves

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What does CHARGE stand for

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What is Charge
Coloboma of the eye
Heart Defects
Atresia Choanae
Retarded growth & dev
Genital Hypoplasia
Ear anomalies & deaf

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Atresia Choanae

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back of the nasal passage (choana) is blocked

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Coloboma

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hole in one of the structures of the eye, such as the eyelid, iris, retina, choroid or optic disc.

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What causes CHARGE?

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Failure to rupture bucconasal membrane

Irregularities in cephalic neural crest migration

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CHARGE gene

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CHD7

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 Lordosis

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Legs bow inward - Achondroplasia

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 Kyphosis

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legs bow outward - Achondroplasia

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Most common type of short limb dwarfism

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Achondroplasia

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spinal stenosis

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narrowing of the spinal cord causing nerve pinching

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Achondroplasia molecular mech

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FGFR3 gain of function mutation causes it to be constitutively active tyrosine kinase activity

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Achondroplasia diagnosis

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3. Diagnosis relies on PCR-RFLP

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What is Rett syndrome

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X linked cognitive impairment- spordic mutations generated in sperm

Disorder of developmental arrest

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Apraxia

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loss of purposeful body movements

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Rett: Atypical Early onset variant is caused by

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CDKL5

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Rett: Molecular Mech

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MeCP2 gene is essential for brain dev

role in forming synapses

silences other genes by binding to methylated CpG dinucleotides (Epigenetic regulation)

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Common Symptoms in Rett

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mobility
speech
repetitive hand movement
cognitive

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Concordant

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: pair of relatives that both have a qualitative trait or quantitative trait of similar magnitude

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iii. Discordant

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pair of relatives where one has a qualitative trait and the other don’t, or quantitative is ate opposite ends of distribution

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- Linkage analysis

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b. Follow inheritance patterns of regions of the genome that coordinates w/disease incidence

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- Association Analysis

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a. Population based
b. Looks for increased or decreased frequency of a particular allele or set of alleles in a sample of affected & control

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syntenic loci

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2 locus that are on the same chromosome

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- Recombination freq

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measure of the distance btw syntenic loci

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- Linkage disequilibrium

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occurrence of specific haplotypes (combinations of alleles) more frequently than the frequency of the individual alleles in the population

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disease odd ratio

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Patient w/allele/ Control w/allele divided by patient w/out allele/Control w/out allele

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- LOD: log of the odds

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Determining whether a phenotype is linked to a particular locus

Likelihood of the data if loci are linked at a particular ϴ / likelihood of the data if loci are unlinked (ϴ = 0.5)

Gives best estimate of recombination freq btw marker & disease locus

c. Values > 3 (1000:1 odds) are considered strong evidence
i.  implies that disease gene locus in near marker

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- Hap Map

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a. Dense collection of SNPs throughout the genome
b. Measures LD btw neighboring markers throughout the genome
c. Some SNPs are significantly different btw populations
d. SNPs group together in LD clusters = LD blocks

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What is Tay Sachs

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progressive loss of CNS

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Tay Sachs: Gene

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HexA- remove & breakdown GM2 gangliosides (glycosphingolipids, cell signaling & part of PM) from the neuron

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TGay Sachs: molecular Mech

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GM2 accumulation
--> neuron cell body distension
--> neuronal cell death
--> brain atrophy

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Tay Sachs: Diagnosis

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- Cherry red macula
- DNA test: restriction endonucleases or ELISA
- Lack of developmental progress
- Hyperacusis: Startled by loud noises

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Hb Kemspey

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i. Enhance Function

: locks hemoglobin in high affinity state

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1. Alpha thalassemias

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b. Loss of Function

i. Protein not produced or is non-functional

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c. Ectopic gene expression

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i. Inappropriate expression in time or place

GAMMA CHAIN PRODUCED IN ADULT

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ii. Dactyllitis

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painful swelling of hands from stroke in small bones

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- Thalassemia

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Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules

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a. Alpha thalassemia

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may occur b/c of unequal crossing over in homologous pairing (deletion / duplication )
iii. May also be caused by mutation in LCR
iv. Loss of 1 alpha not as bad as beta

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b. Beta thalassemia

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i. Mutations-SNPs

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Glu-6-P Dehydrogenase Deficiency:

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- G6PD rate-limiting enzyme of the pentose phosphate pathway
b. regenerates NADPH which is needed for glutathione
glutathione protect the cell from oxidative stress

good against malariea

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Treacher Collins: outcome

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- Tcof-1 gene: Treacle

Leads to death of proliferating cells, --> loss of neural crest cells

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Treacher Collins: molecular mech

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- Tcof-1 gene: Treacle
e. Component of ribosome, RNP complex in the nucleolus
i. Mut --> activation of p53: Tumor Suppressor (stops growth & induces apoptosis)

a. Leads to death of proliferating cells, --> loss of neural crest cells from 1st pharyngeal arch

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Lysch-Nyhan Syndrome: what is it

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X linked recessive 1 gene

deficiency in activity of HPRT
a. Alpha PrPP + Hypoxanthine --> GMP
b. Needed for purine metabolism
too much too much Uric acid may cause neurotoxicity (cognitive impairment)
loss of dopamine in striatum

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Lysch-Nyhan Syndrome: diagnosis

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HPRT enzyme activity assay

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Ataxia-telangiectasia: gene

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ATM:

ds break repair

b. Ser/Thr kinase

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Ataxia-telangiectasia: phenotypes

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RANCID

Radiation sensitivity
Alpha-fetoproteins elevated
Neurological problems
Cancer risk increased
Immune defects
Dilated Blood Vessels

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Ataxia-telangiectasia diagnosis

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ICS-MCB

anuploidy; breaks

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Cystic Fibrosis: mutations & mech

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CFTR -
1. delta F508 don't flod & cant leave ER (Cl transporter)
2. unstable RNA/premature stop
3. nucleotide binding domain of protein
4. defective Cl condcution b/c mut in membrane spaning domain
5 fewer CFTR transcripts

ENaC - higher sweat Cl levles

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Chorea

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involuntary movements from continuous flow of random muscle contractions

Huntington

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Huntington Disease

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4p16.3: Huntingtin gene- CAG repeat in 1st exon

slipped mispairing

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Fragile X

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X(q27.3)
expansion of the CGG repeat in the 5’ UTR of FMR1 gene
-FMRP: transports mRNA’s in dendrites and is involved in protein synthesis regulation

Problem with the FMR1 gene = hypermethylation of CGG and upstream CpG islands lead to silencing, or pt. mutations or deletions in the FMR1 GENE

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Klinefelter syndrome

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XXY due to non-disjunction

Xist - RNA gene on the X chromosome acts as major effector of the X inactivation

AR gene: Xq11.2-12