Block 3 Flashcards
Housekeeping proteins
- Present in virtually every cell or organ
- Fundamental to maintenance of structure and function
- Disease: rarely causes pathological changes in every tissue
- Genetic Redundancy: overlapping jobs/activities - Specialty function: protein is expressed abundantly and serves a specific purpose in that area
Tissue-specific specialty proteins:
- Unique to a tissue(s), only expressed in certain areas of the body
- Disease: restricted to this tissue
- Exception is PKU: brain problems despite the deficiency being in the liver
Enzymopathies
- ** Are almost always recessive***
- *a hereditary disease caused by an inborn error of metabolism that results from an enzyme disorder.**
- Substrates accumulate and products are deficient
- A diffusible substrate often affects many different tissues while non-diffusible (macromolecular) substrates mainly affect the deficient tissue
- One defect will affect multiple activities
Phenotypic Homology:
Diseases due to different enzymes that function in the same area of metabolism
PKU and Hyperphenylalanemia
AR Mut Ch. 12 PAH gene if both allele mutation the one w/ less severy is express
Heel stick test 24+ hr after birth determine lvs if any of toxicity of phenylalanine
Classical PKU
Mutation @ Ch 12 in PAH (phenylalanine hydroxylase) converts phenylalanine–> tyrosine
Accumulation of Phenylalanina
Phenotype:
Mental retardation, organ damage, unusual posture and a compromised pregnancy (mental retardation, microcephaly, heart malformations, and growth impairment in the fetus)
Musty odor in the infant’s diaper from Phenylpyruvic acid deposition
Patients need to avoid proteins, dairy, and eggs
Hyperphenylalanemia
Milder phenotype of a PAH mutation. Chromo 12
ERT = ?
Enzyme Replacement Therapy
Tay Sach
AR - Frameshift Mutation cause by an insertion of 4 bases TATC in exon 11.
Mutation in HexA gene (hexosaminidase A) causes –> Accumulation of GM2Ganglioside by cleavage of N-Acetyl-beta-galactosamine residue from ganglioside
Early onset: 4-6months death by 2-4yrs. Cherry Red Macula, Mental Retardation
Late onset: lower motor neuron deterioration but vision and intelligence remains intact
Mucopolysaccharidoses (MSP)
Build up of GAGs. Urine test may be performed.
Hurler’s Syndrome
Mut in alpha-L-iduronidase @ Ch 4
causes accumulation of GAGs
Phenotype:
Mental & growth retardation, Cornea Clouding, Hearing loss, death by cardiorespiratory failure @ ˜age 10
I Cell Disease
AR, Mut. in N-Acetylglucosamine-1-Phosphotransferase (Doesn’t phosphorylate Mannose to tag it for degradation y lysosome in the golgi) Lack of M6P tag. @ Ch 12
Phenotype:
Unusual facial feature, skeletal changes, severe growth & mental retardation, excess hydrolyses in the body fluids death by age 5-7yrs
Homocystenuria
AR
6 possible mutation that cause accumulation of Cysteine
1. Mut in Cystathione Synthase
2. Metylene blude H4 Folate reductase: impairs Methionine Synthatse
3. Cobalamin metabolism
4. Methyl B12 formation
5. Extracellular transpor: trascobalamin II
6. Cobalamin malabsorption
Phenotype:
Lens dislocation, Mental retardation, osteoporosis of long bones, thromboembolism of veins and arteries
Alpha-1-Antitrypsin Deficiency
AR @ Ch 14
Z allele is common @ 342: Glu->Lys
-17% Presents w/neonatal jaundice of which 20% may dev. cirrhosis.
-Mutant Z protein aggregates in RER of hepatocytes forming long “bead-like” necklaces of mutant polymers
-causes decrease in plasma [enzyme]
Protein experess primarily in the LIVER
Normal funct is to inhibit ELASTASE which is release by resp tract
Elastase normal function is to degrade alveolar wall causing COPD
Smoking aggravates this effects by oxidizing methionine @ 358 reducing a-1-antitrypsin affinity for elastase
Cystic Fibrosis
AR mut in ∆F508 CFTR gene (3nucleotide del of PHE in the NBD1 domain: in the intracellular portion of CFTR protein that doesn’t allow proper folding) @ Ch 7
*DX w/ sweat test: Inc Na+ & Cl-
key:
Chronic Obstructive lung disease dev. as a result of thick mucous (death by pulmonary failure/infection)
Pancreatic enzyme are deficiente & prevents normal digestion hence greasy foul-smelling stools.
**Males are sterile due to lack of Vas deferens
Acute Intermitent Porphyria
AD Mutation in PBDG gene @ Ch 11
Occurs w/ exposure to BARBITUATES, steroids H, -> Increases synthesis of P450 (heme cofactor)
Decrease [Heme] in liver –> loss of feedback inhibition of ALA synthase. Hence increase in synthesis of ALA & PBG.
Causes HEME deficiency & a secondary increase in Delta ALA Synthase lvs.
PHENOTYPE:
Neorological Problems: parasthesia, confusion, hallucinations, psychosis, abdominal pain & vomiting
Familial Hypercholesterolemia & Hyperlipidemia
AD 4 diff. types of mutation may occur;
- LDL receptor @ Ch19
- LDL receptor binding domain of ApoB100 @ Ch 2.
- PCSK 9 protease causes degradation of LDL receptor @ Ch 1
- ARH adaptor protein: inhibits the endocytic machinery of the coated pit @ Ch 1
DMD/BMD
DELETIONS
Allelic Heterogeneity
Deficient/defective or absence of Dystrophin
@NH2 terminus it assoc w/actin
@COOH terminus binds w/ sarcoglycans etc.
Links the ECM (laminin) to the actin cytoskeleton
Duchenne’s Muscular Dystrophy (DMD)
QUANTITY
X-linked recessive
lack of dystrophin by a del that causes a framshift mutation
1/3 de novo mut
2/3 carrier mothers
boys normal first yr then onset @ 3-5 with progressive proximal l muscle weakness, gower maneuver, pseudo hypertrophy of the calves from replacement of FAT & fibrous connective tissue, Low IQ High Creatinine Kinase, wheelchair bound by age 12 death by 18.
Becker’s BMD
QUALITATIVE
X-linked recessive
In frame deletions->translation occurs –> truncated protein
Less severe reading frame is maintain but reduce amount and quality of dystrophin is found
Onset by age 11 DX if still waking by age 16
Ehlers-Danlos Syndrome (EDS)
Mutation in Collagen
Type 1&2 = COL5A1 & COL5A2 AD
Type 3= Hypermobility AD
Type 4= decrease reticulin (TYPE 3 Collagen) COL3A1
Type 6=AR deficiency in LYSYL Hydroxylase
Type 7=Can’t turn pro collagen–> Collagen
Type 8 = dermatosporaxsis
Osteogenesis Imperfecta (OI)
Problem in Collagen assembly
NULL=reduce amount
Missense glycine substitutions=alter the structure hence quality
the closer to COOH terminus the mutation the more severe the phenotype
OI
AD
Type 1: NULL amount is reduce but structure is normal. Blue/purple/gray Sclera, brittle bones, loose joints, NO Deformity Mildest form of OI
Type 2: Missense toward the COOH terminus = most sever form. New Mutation, Dark sclera and deformity.
Type 3: Missense Fracture present @ birth, bony deformity, Dentinogenesis imperfecta, blue sclera, hearing loss
Type 4: Missense. Normal Sclera mild to moderate bone deformity, Short Stature hearing loss and dentinogenesis imperfecta
Alzheimer Disease (AD)
@ Ch 21 Phenotype: progressive inability to remember facts and events that progresses to an inability to recognize friends & family, rigidity, mutism, incontinence etc. *Extracellular: ß-Amyliod plaques *Intracellular: hyperphosphorylated TAU protein Alpha secretase = good Gamma & Beta = good when AB40 is cleave Gamma & Beta = BAD when AB42 is cleave In AD High lvs of AB42 found
PSEN-1
Mutation results in Gaind of Funct which in turn Increase AB42/AB40
Mutation found in 50% of FAD @ Ch 14
Age of Onset 35-60yr
PSEN-2
1-2% of FAD Maximal expression seen outside the brain Ch 1 missense mutation contribute to AD AGE of onset: 40-85yrs
ApoE
Connected to AD through components of senile plaques @ Ch19
Mitochondrial DNA
Ring DNA structure. Stricly Maternal inheritance
3 types of mutations:
Missense in coding regions: alter act of oxphos
Point mutation: in rRNA &tRNA genes that impair translation of kit proteins
Rearrangements that cause deletions/duplication
Phenotype Mit Disorder
WIDESPREAD
Degree of heteroplasmy contributes to the pleotropy and variable expressivity
Homoplasmy is found largely for some syndromes
Leber’s Hereditary Optic Neuropathy LHON
Phenotype:
rapid, painless bilateral loss of central vision due to optic nerve atrophy in young adults
High penetrance in males about 50% of males carriers but only 10% females carriers dev symptoms
Alcohol and tobacco use increase probability of blindness in carriers
MERRF Myoclonic epilepsy w Ragged-RED muscle fibers
Childhood onset
A–>G transition @ 8344 detected in blood leukocytes
Myoclonus, epilepsy, ataxia, RAGGED RED M fibers, Hearing loss short stature, optic atrophy cardiomyopathy wakness dementia
MELAS Mitochondrial Encephalomyopathy lactic acidosis and stroke like episodes
Presents early in childhood
A–>G transition
Wakness, pain, headaches, loss of appetite, vomiting, seizures, clonus, ataxia, hearing loss, hear/hidney problems, DM
Stroke like episodes before 40
vision abnormalities appear like migraines temp muscle wakens on one side of the body
Build up of lactic acid–> abdominal pain, vomiting, fatigue, muscle weakness
Repeated disorders
Anticipation=Pattern of inheritance where ind. in the most recent gen. of the pedigree dev the disease @ an earlier age & or w/ greater severity as it is transmitted through a family 3 classes of diseases; class 1: expansion of noncoding repeats that cause LOF (i.e. Fragile X & Friedrich Ataxia) Class 2: disorders resulting from expansions of noncoding repeats that confer novel properties on the RNA (i.e. Myotonic Dystrophy 1&2 & Fragile X assoc tremor /ataxia syndrome) Class 3: diseases due to repeat expansion of a codon (i.e. Huntington D & Spinocerebelar ataxias)
Huntington Disease
AD repeat of CAG Normal 30< Pre 29-35 Affected 40-121 Insoluble aggregates of the nut protein Toxic lvs. of glutamine Neurodegenerative disorder assoc. w/ **Chorea, Dysphagia, loss of cognition & psychiatric abnormalities**
Fragile X Syndrome
CGG trinucleotide repeat in 5’ UTR of FMR1 gene
Normal <60
Unstable60-200
Affected 200 +
excessive methylation of cytosine in the promoter
Silencing the gene leading to reduce FMR1 expression.
Hypergonadism, fat
Fragile X assoc w tremor & ataxia syndrome
Late onset progressive cerebellar ataxia & intention tremor due to the formation of intranuclear inclusions
2-5x increase in the lv of FMR1 mRNA present representing a GAIN of Function of FMRP
MR & Learning abnormalities
Freidrich Ataxia
AR mutation repeating GAA in the first intron of the frataxin protein, inhibition of transcriptional elongation.
Normal 200-1700
Involed in iron metabolism & loss of frataxin act is assoc w/ increase iron in the mitochondria impaired heme synthesis and reduce act of complex 1 & 2 in oxphos chain
Cardiomyopathy , Type 2 Diabetes and spinocerebellar ataxia
Myotonic Dystrophy 1
AD repeating CTG (CUG in mRNA) in the 3’ UTR of DMPK @ Ch 19
Normal <30
Unstable 50-80
Affected 80-2000
More repeats = more severe
Myotonia, cardiac conduction defects testicular atrophy insulin resistance cataracts and MR
Myotonic Dystrophy 2
Repeat of CTT in the Zinc Finger protein 9 gene
