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Pyrimidine Synthesis
1st step: Carbamoyl Phosphate + Aspartate --> Carbamoyl aspartate. Catalyzed by Asapartate transcarbomoylase.
Subsq. steps: Ring closure occurs with loss of water followed by oxidation --> Orotic acid.
Next steps: Orotic acid + Ribose-5-P --> Orotidylic acid --> is decarboxylated by Orotidylate decarboxylate to yield Uridylic acid.
CO2 that is evolved is derived from the alpha carboxyl group of aspartate.
Purine synthesis
Glutamine, Glycine, N10-formyltetrahydrofolate = all used in purine synthesis.
Male to male trasmission.
Multiple generations affected
Autosomal dominant
Mismatch Repair
1. HNPCC type I: these pts are deficient in the mismatch repair protein MSH2 --> DNA and Microsatellite instability.
Causes one daughter cell to have 24 ch's while the other will have 22 ch.
When a gamete with normal 23 ch combines at fertilization --> embryo will have 47 ch (TRISOMY)
or 45 Ch (Monosomy).
Nondisjunction can occur in either the first or second meiotic division.
Sturge Weber Disease
Includes vascular lesion that unlike the strawberry nevus dont regress with age.
Eg. Facial lesion (Port wine stain)
- vascular lesions of the meninges (leptomeningeal angiomatosis) etc.
Tay-Sachs disease
Result of a frameshif mutation (insertion of 4 nts into the coding region of the gene for the alpha subunit of the Hexosaminidase A gene)
- Cherry Red spot
- commonin Ashkenazi jews (carrier rate is 1/25)
- No effective treatment and survival beyond 4 years is rare.
Nutrient deficiencies
1. Ca def in children --> osteopenia/osteoporosis
2. Fe def - hypochromic, microcytic anemia
3. Mg --> uncommon but can cause dec reflexes, n blunts the PTH response to Hypocalcemia
4. Se --> rare, but may cause a reversible form of Cardiomyopathy
5. Iodine - CRETINISM! (Pot bellied, mentally retarded, thick tongue)
Achondroplasia - Autos dominant disorder due to point mutations of the gene coding for FGF(fibroblast growth factor) - Receptor 3. --> results in constant activation of FGF-R3 ==> Inhibits chondrocyte proliferation.
Signs: abnormally shortened limbs, bulging forehead.

Usually, result from de novo mutations.
Delay in motor development. Spasticity. Compulsive Nail biting and lips, head banging. Arthritis at puberty and death from renal failure.
Lesch-Nyhan syndrome - X-linked dz due to def in purine salvage enzyme HPRT.
Leads to Excessive de novo purine syntheis, Hyperuricemia and the signs n symptoms.
- often striking self-mutilatory behavior.
- Hyperuricemia --> gouthy arthritis, urate stone formation, n urate Nephropathy. Rx: Allpurinol.

no treatment for neurologic/psychiatric presentation.
Rb gene and Retinoblastomas
Rb gene = classic Tumor suppressor gene. The Rb protein binds to and sequesters the sp. transcription factor E2F and htus inactiving E2F.
Active E2f increases transcription of a variety of proteins that move the cell from the G1 to S phase of the cell cycle.
Children born w 13q14 deletion have only one Ch encoding Rb; thus a single hit (eg loss of a ch druing somatic mitosis) is enuf to knockout Rb production --> Retinoblastoma.
Another TSG.
Activates apoptosis in the presence of significant DNA damage. P53 activity prevents the cell from progressing thru the cell cycle and activates transcription of DNA repair genes.
Def: Galactose-1-P uridyltransferase, necessary for the metabolism of the galactose derived from milk lactose.

Suspect condition in infants w:
Growth failure, cataracts, liver disease, aminoaciduria and mental retardation.
A reducing sugar (galactose) is usually present in the urine.
Rx: strict dietary lactose restriction (milk and other non-dairy lactose contianing products)
Inherited mental retardation + Chromosomal breakage (on testing with MTX)
Fragile X

Chromosomal breakage!!!
This heritable Mental retardation condition is assoc with Ch'l breakage. Break point is q27.3 on the Xch.
Fragile x shows anticipation like Huntingtons.
Test: Culturing lymphocytes in either folate deficient medium or with chemical agents such as Methotrexate that tend to break chromosomes. Atleast, 4% of metaphase Ch's must show the sp. break-point on the X ch.

Trisomy 13, 18, 21 are all assoc with mental retardation but not Ch breakage syndromes.
Acute Intermittent Porphyria
Def: of PBGD (porphobilinogen Deaminase) aka uroporphyrinogen decarboxylase.
Results in Serum accumulation of Pophobilinogen (PGB), ALA and porphyrins.
Also, increases in urine ALA and PBG (makes urine port wine color)

Sxs: 5Ps (Painful abdomen, Pink urine, Polyneuropathy, Psychological disturbances, Ppt'd by drugs)

Precipitated by certain evnt'l factors, drugs or changes in nutritional state.
AA precursors
Arginine --> NO
Glutamate --> GABA via vit B12
Tryptophan --> Niacin --> NaD+/NADP+
---> Serotonin
--> Melatonin

Phe --> Tyr --> Dopa --> (melanin &) Dopamine --> NE --> Epi

Glycine is a nt, not a precursor.
Barr body
Barr body = X chromatin body IS an inactivate X ch seen as a small, perinuclear, dark-staining dot in somatic cells with 2 or more X ch's including 1) Normal females 2) XXY - kleinfelters etc. As in normal females, one of the X ch becomes a barr body in Kleinfelter's syndrome.

Need more than one X ch for the other to become inactivated.

Classic trisomies (13, 18, 21) which are not X-linked dont express any barr bodies. Their extra ch is expressed in its entirety.
Gene frequency of an X-linked recessive dz (eg. Duchenne's)
Gene freq of an X-linked dz in the population = Incidence of the X-linked recessive dz in the Male portion of the population.

Males have only 1 single x ch, each affected male has one copy of the disease causing recessive mutation.

Eg: Incidnece of Ducehnnes is 1/3000.
Gene frequency = 1/3000!
Junctional Complexes (JCs)
JC's are critical to Epithelial cell organization.

Formation of JC's relies on the homotypic interaction btw E-Cadherin proteins on adjacent cells. This intrxn initiates the formation of Zona Adherens, including signaling pathways, which are then activated to initiate the formation of Zona Occludens and Desmosomes.

Connexins form Gap junctions - not a part of Jxt'l complexes.

Desmoglein - a cadherin sp. to desmosomes. Lack of it only affects desmosome formation.

Occludin - a TM protein linker that forms the tight junctions of Zona Occludens. Doesnt effect other elements of JC.

Tonafilaments (Intracellular Keratin intmdt. filaments) connect the desmosomes in epidermal cells.
Spontaneous Abortion due to a trisomy.
Trisomy 16, 13, 18, 21?
Trisomy 16!

Almost half of spontaneous abortions are due to Major ch'l defects - most commonly Trisomy 16, triploidy (due to fertilization of an egg by 2 sperm) and 45 (X,O) Turners.
Trisomy 16 and Triploidy dont produce viable offspring.
A small chapoeron protein in the RER that monitors protein folding. Calreticulin binds to misfolded proteins and prevents them from being exported to the Golgi.

Eg. LDL R is a membrane protein expressed on cell surface. Thus its syntheis starts in the cytosolo on free ribosome but is completed on ribosomes bound to the RER during import into the RER.

LDL R doesnt dimerize.

Presence of Mannose-6-P targets soluble enzymes for delivery to lysozymes. but LDL is expressed on cell surface.
Clinitest reaction
Clinitest tablets detect elevation of reducing sugars (Galactose, Glucose, Fructose).
Confined Placental Mosaicism
Occurs due to a mutation occurring within trophoblast or extraembryonic precursor cells of the inncer cell mass.

IMP cause of IUGR
Uniparental Disomy
Can cause Angelman's. (nromally caused by a deletion of maternal Ch15). Now, the embryo receives 2 copies of the paternal CH15 without the maternal Ch15 to balance the paternal contribution.

Sxs: Females, Ataxia, Seizures and inappropriate Laughter.
Substitution mutations
Can occur as
1) Transversion - A purine (AG) is substituted for a pyrimdien (CUT) or vice versa

2) Transition - Purine replaced by a purine OR a PYr replaced by a Pyrimidine.
Fatty acid oxidation

Eg: # of ATPs per Laurate (12C) oxidation
Eg. Lauric Acid (12 C)
1. Activation of Laurate requires 2 high energy phosphate bonds (-2)
Laurate + CoA + ATP --> Lauryl CoA + AMP + PPi
PPi + H20 --> 2 Pi

2. LaurylCoA + 5CoA --> 6 Aceetyl CoA + 5 FADH + 5 NADH (25 ATP)

3. 6AcetylCoA --> 12 ATP/AcetylCoA x 6 = 72 ATP

Thus, total ATP = (72+25 - 2) = 95!
Pericentric inversion
Recombination event - an inversion that involves the centromere.

Inversions that dont include the centromere = Paracentric inversions.

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