Biochemistry Flashcards
Heterochromatin
Condensed, appears darker on EM. Sterically inaccessible, thus transcriptionally inactive. Increased methylation, decreased acetylation.
Euchromatin
Less condensed, appears lighter on EM. Transcriptionally active, sterically accessible.
Collagen: Type I
Most common (90%) - Bone (made by osteoblasts), Skin, Tendon, dentin, fascia, cornea, late wound repair
Collagen: Type II
Cartilage (including hyaline), vitreous body, nucleus pulposus
Collagen: Type III
Reticulin - skin, blood vessels, uterus, fetal tissue, early wound repair
Collagen: Type IV
Basement membrane (basal lamina), lens.
Myotonic Dystrophy
Autosomal dominant. CTG trinucleotide repeat expansion in the DMPK gene -> abnormal expression of myotonin protein kinase -> myotonia (eg, difficulty releasing hand from handshake), muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia.
Fragile X Syndrome
X-linked dominant inheritance. Trinucleotide repeat in FMR1 gene -> hypermethylation -> decreased expression. Most common inherited cause of intellectual disability (Down syndrome is the most common genetic cause, but most cases occur sporadically).
Findings: post-pubertal macroorchidism (enlarged testes), long face with large jaw, large everted ears, autism, mitral valve prolapse, hypermobile joints.
Down Syndrome
trisomy 21 (nondisjunction in meiosis) Findings: intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, incurved 5th finger, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg, ASD), Brushfield spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein), increased risk of AML/ALL. 95% of cases due to meiotic nondisjunction (increased with advanced maternal age; from 1:1500 in women <20 to 1:25 in women >45 years old). 4% of cases due to unbalanced Robertsonian translocation, most typically between chromosomes 14 and 21. Only 1% of cases are due to postfertilization mitotic error.
Edwards Syndrome
trisomy 18
Findings: Prominent occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists with overlapping fingers, low-set ears, micrognathia (small jaw), congenital heart disease, omphalocele, myelomeningocele. Death usually occurs by age 1 year.
Patau Syndrome
trisomy 13
Findings: severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, polycystic kidney disease, omphalocele. Death usually occurs by age 1.
Osteogenesis Imperfecta
Genetic bone disorder (brittle bone disease) caused by a variety of gene defects (most commonly COL1A1 and COL1A2).
Most common form is autosomal dominant with decreased production of otherwise normal type I collagen. Manifestations include:
Multiple fractures and bone deformities after minimal trauma (eg, during birth)
Blue sclerae due to the translucent connective tissue over choroidal veins
Some forms have tooth abnormalities, including opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta)
Conductive hearing loss (abnormal ossicles)
Ehlers-Danlos Syndrome
Faulty collagen synthesis causing hyperextensible skin, hypermobile joints and tendency to bleed (easy bruising). Multiple types. Inheritance and severity vary. Can be autosomal dominant or recessive. May be associated with joint dislocation, berry and aortic aneurysms, organ rupture. Hypermobility type (joint instability): most common type. Classical type (joint and skin symptoms): caused by a mutation in type V collagen (eg, COL5A1, COL5A2). Vascular type (fragile tissues including vessels [eg, aorta], muscles, and organs that are prone to rupture [eg, gravid uterus]): mutations in type III procollagen (eg, COL3A1).
Menkes Disease
X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A, vs ATP7B in Wilson disease). Low copper levels (vs high levels in Wilson disease). Leads to low activity of lysyl oxidase (copper is a necessary cofactor) -> defective collagen. Results in brittle, “kinky” hair, growth retardation, hypotonia, increased risk of cerebral aneurysms.
Lesch-Nyhan Syndrome
Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis.
X-linked recessive.
Findings: intellectual disability, swollen and painful joints, self-mutilation, aggression, hyperuricemia (orange “sand” [sodium urate crystals] in diaper), gout, dystonia, macrocytosis.
HYPERSEGMENTED NEUTROPHILS
Treatment: Allopurinol or febuxostat (2nd line).
Microfilaments
Muscle contraction, cytokinesis
Intermediate Filaments
Maintain Cell Structure
Microtubules
Movement, cell division
Marfan Syndrome
autosomal dominant (with variable expression) connective tissue disorder affecting skeleton, heart, and eyes. FBN1 gene mutation on chromosome 15 results in defective fibrillin, a glycoprotein that forms a sheath around elastin. Findings: tall with long extremities; pectus carinatum or pectus excavatum; hypermobile joints; long, tapering fingers and toes (arachnodactyly); cystic medial necrosis of aorta; aortic root aneurysm rupture or dissection (most common cause of death); mitral valve prolapse. Subluxation of lenses, typically upward and temporally (vs downward and medially in homocystinuria).
Southern Blot
DNA is cleaved, separated by electrophoresis and transferred to a filter. Filter is exposed to radiolabeled probe that anneals to it’s complementary strand.
Resulting double-stranded, labeled DNA when filter is exposed to film.
Northern Blot
RNA
Western Blot
protein
Southwestern Blot
DNA-binding proteins
Codominance
Both alleles contribute to the phenotype of the heterozygote
Variable expressivity
Patients with the same genotype have varying phenotypes
Incomplete penetrance
Not all individuals with a mutant genotype show the mutant phenotype.
%penetrance x probability of inheriting genotype = risk of expressing phenotype.
Pleiotrophy
One gene contributes to multiple phenotypic effects.
Anticipation
Increased severity or earlier onset of disease in succeeding generations.
Loss of heterozygosity
If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.
Dominant negative mutation
Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.
Linkage disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.
Mosaicism
Presence of genetically distinct cell lines in the same individual.
Somatic mosaicism - mutation arises from mitotic errors after fertilization and propagates through multiple tissues and organs.
Gonadal mosaicism - mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline) mosaicism.
Locus heterogeneity
Mutations at different loci can produce a similar phenotype.
Allelic heterogeneity
Different mutations in the same locus produce the same phenotype.
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease.
Uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heterodisomy (heterozygous) indicates a meiosis I error. Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.
Prader-Willi Syndrome
PATERNAL DELETION
Maternally derived genes are silenced.
Disease occurs when the paternal allele is deleted or mutated.
Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
Chromosome 15 of paternal origin
Angelman Syndrome
MATERNAL DELETION
Paternally derived UBE3A is silenced
Disease occurs when the maternal allele is deleted or mutated
Seizures, ataxia, severe intellectual disability, inappropriate laughter
UBE3A on maternal copy of chromosome 15
Cystic Fibrosis
Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508. Most common lethal genetic disease in Caucasian population.
CFTR encodes an ATP-gated Cl channel that secretes Cl in lungs and GI tract, and reabsorbs Cl in sweat glands. Most common mutation -> misfolded protein -> protein retained in RER and not transported to cell membrane, causing decrease Cl (and H2O) secretion; increase intracellular Cl results in increase Na reabsorption via epithelial Na channels (ENaC) -> increase H2O absorption -> abnormally thick mucus secreted into lungs and GI tract. Increase Na reabsorption also causes more negative transepithelial potential difference
Duchenne
X-linked disorder typically due to frameshift deletions or nonsense mutations -> truncated or absent dystrophin protein -> progressive myofiber damage. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudeohypertrophy of calf muscles due to fibrofatty replacement of muscle. Waddling gait.
Onset before 5 y/o. Dilated cardiomyopathy is common cause of death.
Becker
X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne.
Onset in adolescence or early childhood.
Genetic disorders by chromosome: 4
ADPKD (PKD2)
Achondroplasia
Huntington Disease
Genetic disorders by chromosome: 5
Cri-du-chat syndrome
Familial Adenomatous polyposis
Genetic disorders by chromosome: 7
Williams Syndrome
Cystic Fibrosis
