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What are microRNAs

-small non-coding RNA molecules that inhibit gene expression
-account for about 5% of the human genome
-once processed, single strands of miRNAs are incorporated into a multiprotein complex (RNA-induced silencing compex; RISC)
-the miRNA basepairs with its target, causing the RISC to repress the translation of the mRNA or cause mRNA cleavage, silencing the gene from the target mRNA at a posttranscriptional level


Loss of function mutations in AD disorders

-more common
-affect regulatory proteins or subunits of multimeric proteins that may act through a dominant negative effect


Features of X-linked disorders

-the majority are recessive (notable exception: Vit D resistant rickets)
-sons of affected men are not affected but daughters have a 1/2 chance of being carriers
-carrier women usually not affected but due to random inactivation of one x chromosome, she may show the trait to a variable degree


4 categories of single gene disorders

-enzyme defects
-membrane receptor/transport defects
-nonenzymatic protein defects
-defects causing unusual reactions to drugs


Examples of enzyme defects in Mendelian disorders

-accumulation of a substrate that is toxic (e.g. lysosomal storage diseases)
-insufficient production of the end product (e.g. albinism)
-failure to inactivate a tissue damaging substrate (e.g. lack of A1AT resulting in excessive neutrophil elastase activity)


Which is better, Niemann-Pick A or B?

B, usually they survive into adulthood because they lack CNS involvement while type A die from marked accumulation of sphingomyelin and progressive wasting by 3 years of age


EM findings in Niemann-Pick A

-"zebra bodies": concentric lamellated myelin figures in the cytoplasm


Niemann Pick type C

-mutations in NPC1 and NPC2
-primarily a defect of lipid transport
-clinically heterogenous
-cells accumulate cholesterol and gangliosides


Gaucher disease

-most common lysosomal storage disease
-autosomal recessive mutations in gene encoding glucocerebrosidase
-three types: 1) non-neuropathic (splenic and skeletal involvement, 2)acute neuronopathic, 3)mixture between 1 & 2


Histologic appearance of Gaucher cells

-unlike other lysosomal storage disorders, aren't vacuolated but rather have a wrinkled tissue paper fibrillary appearance
-PAS positive
-EM: bilayers of stored lipid in distended lysosomes



-deficiencies of lysosomal enzymes for degrading mucopolysaccharides (GAGs)
-accumulate deramatan sulfate, heparan sulfate, keratan sulfate and chondroitan sulfate
-all AR except Hunter syndrome which is X-linked recessive


Glycogen storage diseases

-deficiency in enzymes involved in the synthesis or sequential degradation of glycogen
-hepatic forms (enzymes involved in hepatic glycogen degradation, e.g. von Gierke disease; hepatomegaly and hypoglycemia)
-myopathic forms, deficiency in enzymes involved in glycolysis (McArdle disease, muscle cramps after exercise and high blood lactate)
-those involved with deficiency of acid maltase or lack of branching enzymes, e.g. Pompe disease; cardiomegaly prominent in all


Discuss karyotyping

-arrest dividing cells in metaphas (e.g. with Colcemid): metaphase spread
-usually involves staining with Giemsa (G-banding)


Anaphase lag

-one homologous chromosome in meiosis or one chromatid in mitosis is lags behind and is left out of the nucleus, resulting in one normal cell and one monosomic cell



-during gametogenesis, gametes are either n+1 or n-1



-results from mitotic errors early in development producing two or more populations of cells with different chromosomal complements
-can occur during the cleavage of the fertilized ovum or in somatic cells


Features of chromosome 22q11.2 syndrome

-variable but include congenital heart defects, palatal abnormalities, facial dysmorphism, developmental delay, T cell immunodeficiency and hypocalcemia
-increased risk for psychotic illnesses (25% of adults with this syndrome develop schizophrenia)
-diagnosed by detection of the deletion by FISH
-possible related to loss of TBX1 (from this region), which is expressed in the pharyngeal mesenchyma and has PAX9 as its target, which controls palata, parathyroid and thymic development


Lyon hypothesis

1) only one X chromosome is genetically active
2) the other X of either maternal or paternal origin undergoes heteropyknosis and is rendered inactive
3) inactivation of either the maternal or paternal X occurs at random on around day 16 of embryonic life
4) inactivation of the same X persists throughout all the cells derived from that precursor
-the inactive X is seen as the Barr body in the interphase nucleus in contact with the nuclear membrane


Features of disorders involving sex chromosomes

-subtle chronic problems relating to sexual development and fertility
-more X's, higher chance of intellectual retardation
-may not be diagnosed until puberty


Features of Klinefelter syndrome

-eunuchoid habitus
-low testosterone with atrophic testes and small penis
-slightly lower IQ than normal
-increased incidence of DM2 and metabolic syndrome
-increased risk of mitral valve prolapse
-increased risk of breast cancer, extragonadal germ cell tumors and autoimmune diseases


Features of Turner syndrome

-cystic hygroma
-congenital heart disease (coarctation and bicuspid aortic valve)
-lack of secondary sex characteristics and amenorrhea
-short stature
-usually normal IQ
-glucose intolerance (worsened by giving growth hormone)


Features of trinucleotide repeat syndromes

-proclivity to expand depends on the sex of the transmitting parent (oogenesis in fragile X, spermatogenesis in Huntington)
-expansion of trinucleotides including C and G
-expansions may occur in coding (Huntington) or noncoding (Fragile X) regions


Carrier males

-males who have a fragile X mutation, e.g., but are phenotypically normal, and pass their mutation to all of their daughters
-a.k.a. normal transmitting males


Features of mitochondrial disorders

-all mtDNA inherited from mother
-many copies of mtDNA in each mitochondrion and mutations may not effect all copies (heteroplasmy); a minimum "threshold" of deleterious copies required to manifest the disorder
-during cell dision, the mtDNA is randomly distributed to daughter cells so there is lots of variability in the proportion of normal and mutant DNA, resulting in variable expressivity of these disorders
-mtDNA encodes mostly genes involved in oxidative phosphorylation, so effected organs are those relying on this, such as brain, skeletal and cardiac muscle, liver and kidneys
-e.g. Leber hereditary optic neuropathy


Define maternal imprinting

-transcription silencing of the maternal allele


When does imprinting occur?

-in the ova or sperm before fertilization, therefore it is stably transmitted to all somatic cells


How does imprinting occur?

-DNA methylation at CG nucleotides


Mechanisms of epigenetic effects

-DNA methylation
-histone deacetylation
-histone methylation



-mutation of paternal chr 15 with an imprinted maternal chromosome
-hyperphagia, mental retardation, obesity, hypogonadism


Angelman syndrome

-deletion of maternally derived region on chromosome 15 with the paternal gene imprinted
-mental retardation, ataxia, seizures, laughter