Genetics/Biochemistry Flashcards
What is pleiotropy?
The occurrence of multiple, seemingly unrelated phenotypic manifestations (e.g. homocystinuria - skeletal abnormalities, lens dislocation, intellectual disabilities, vascular thromboses)
Supplementation with which vitamin may help improve the symptoms of maple syrup urine disease?
Thiamin (B1) - cofactor for branched-chain alpha-ketoacid dehydrogenase. This part of several enzymes referred to as the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC). This is required for degredation of branched-chain amino acids (leucine, isoleucine, and valine). Branched-chain alpha-ketoacid dehydrogenase requires 5 cofactors: Thiamine, Lipoate, Coenzyme A, FAD, NAD (“Tender Loving Care For Nancy”).
What are the stop codons?
UAA, UAG, & UGA
What enzyme is deficient in Ehler’s-Danlos syndrome?
Can be caused by a deficient in procollagen peptidase, which is the enzyme responsible for cleaving terminal propeptides from procollagen in the extracellular space (N- & C- terminal peptides are cleaved)
What are the DNA signals for splicesomes to remove introns.
GU at the 5’ splice site and AG at the 3’ splice site
Where are enhancer sequences located?
They can be upstream or downstream of the gene, or even within introns or on separate chromosomes from the target gene.
What are the nonpolar, hydrophobic amino acids?
Alanine, valine, leucine, isoleucine, phenylalanine, proline and glycine. These are frequently components of the transmembrane domain of proteins.
Which RNA polymerase functions exclusively in the nucleolus?
RNA polymerase I. It exclusively transcribes the 45S pre-rRNA gene into a single template that is subsequently processed into mature 18S, 5.8S and 28S rRNAs.
The nucleolus of malignant cells is often prominent due to the large number of active rRNA genes.
What is MERRF?
Myoclonic epilepsy with ragged red fibers. Mitochondrial inheritance.
What diseases are inherited via mitochondrial inheritance?
Myoclonic epilepsy with ragged red fibers (MERRF), Leber optic neuropathy (blindness), and mitochondrial encephalopathy with stroke-like episodes and lactic acidosis (MELAS)
What is Jervell and Lange-Nielsen syndrome?
An autosomal recessive disorder characterized by profound bilateral sensorineural hearing loss and congenital long QT syndrome. It is due mutations in genes that encode alpha and beta subunits of voltage-gated potassium channels (e.g. KCNA1, KCNE1).
How is diagnosis of methylmalonyl-CoA mutase deficiency made?
Elevated urine methylmalonic acid and propionic acid are diagnostic. This causes a metabolic acidosis which leads to an increased metabolic rate causing hypoglycemia, increased ketones (increased fat metabolism, increases the anion gap), and hyperammonemia. Presents in the neonatal period with poor feeding and lethargy.
The enzyme is involved in branched-chain amino acid metabolism. Uses B12 as a cofactor.
What are features of arginase deficiency?
Progressive development in childhood of spastic diplegia (stiffness of the lower extremities), abnormal movements, and growth delay in the setting of elevated arginine levles. Arginase is part of the urea cycle and produces urea and ornithine from arginine.
What hereditary enzyme deficiency in heterozygotes predisposes patients to maturity-onset diabetes of the young?
Glucokinase. This can be worsened by pregnancy-induced insulin resistance.
What blood disorder do glycolytic enzyme deficiencies (e.g. aldolase A, enolase, phosphofructokinase, pyruvate kinase) cause?
Hemolytic anemia, as RBCs rely completely on anaerobic glycolysis for energy production.
What does calcium bind to in skeletal muscle?
Troponin
What diseases does multiple endocrine neoplasia type 1 (MEN 1) predispose patients to?
Primary hyperparathyroidism (hypercalcemia), pituitary tumors (prolactin, visual defects), and pancreatic tumors (especially gastrinomas - Zollinger-Ellison syndrome).
What diseases does multiple endocrine neoplasia type 2A (MEN 2A) predispose patients to?
Medullary thyroid cancer (calcitonin), pheochromocytoma, parathyroid hyperplasia.
What diseases does multiple endocrine neoplasia type 2B (MEN 2B) predispose patients to?
Medullary thyroid cancer (calcitonin), pheochromocytoma, mucosal neuromas/marfanoid habitus.
What are some common conditions that demonstrate polygenic inheritance patterns?
Androgenetic alopecia, epilepsy, glaucoma, hypertension, ischemic heart disease, schizophrenia, Type II DM.
What molecules is riboflavin (vitamin B2) a precursor for?
Riboflavin is first phosphorylated to become flavin mononucleotide (FMN), which can be further phosphorylated to flavin adenine dinucleotide (FAD). FAD acts as a cofactor with succinate dehydrogenase (gets reduced so it can participate in the electron transport chain as FADH2). Deficiency leads to glossitis, cheilitis, angular stomatitis, seborrheic dermatitis, eye changes (e.g. keratitis, corneal neovascularization), and anemia.
What is the most common cystic fibrosis defect?
ΔF508 mutation. This causes a 3-base pair deletion which impairs post-translational processing leading to misfolding and improper glycosylation of the CFTR protein. As a result, the abnormal protein is targeted for proteasomal degradation, preventing it from reaching the cell surface.
What is the manifestation of ornithine transcarbamylase (OTC) deficiency?
It is the most common urea cycle disorder. It results in excess carbamoyl phosphate, which stimulates pyrimidine synthesis. An intermediate product in this pyrimidine synthesis pathway is orotic acid which accumulates and results in increased urinary orotic acid. These patients also have hyperammonemia due to impaired ammonia excretion (OTC is part of the urea cycle). Ammonia is neurotoxic and can cause episodes of vomiting and confusion/coma. Tachypnea also occurs due to cerebral edema from ammonia buildup, resulting in central hyperventilation and respiratory alkalosis. Metabolic decompensation is often triggered by illness, fasting, or increased protein intake.
What process is the enzyme glycerol kinase involved in?
The breakdown of glycerol to dihydroxyacetone phosphate (DHAP), which can then be used for gluconeogenesis or glycolysis.
Triglycerides stored in adipose tissue are metabolized to free fatty acids and glycerol by hormone-sensitive lipase in response to low insulin and high catecholamine levels. Adipocytes are unable to metabolize glycerol, so it is secreted into the circulation and transported to the liver, where it is phosphorylated to glycerol-3-phosphate by glycerol kinase. Glycerol-3-phosphate is subsequently converted by glycerol-3-phosphate dehydrogenase to DHAP.
What is the Kozak consensus sequence?
Found in eukaryotes used to initiate translation of mRNA (analogous to the Shine-Dalgarno sequence in E. coli). It is defined by the following sequence: (gcc)gccRccAUGG, where R is either adenine (A) or guanine (G). Among other factors, a purine (A or G) positioned 3 bases upstream from AUG appears to play a key role in this initiation process.
What is the Shine-Dalgarno sequence?
Found in prokaryotes. Used to initiate translation of mRNA. The sequence is AGGAGGU.
What is Friedreich ataxia?
An AR disorder caused by a mutation of the frataxin (FXN) gene (increased GAA trinucleotide repeats), which codes for an essential mitochondrial protein involved in the assembly of iron-sulfur enzymes. This causes decreased mitochondrial energy production and increased oxidative stress, resulting in degeneration of neural tracts (dorsal column and dorsal root ganglia [loss of position and vibration sense], lateral corticospinal [spastic muscle weakness], and spinocerebellar [ataxia] tracts) and peripheral nerves. Patients also get kyphoscoliosis and foot abnormalities (pes cavus), as well as hypertrophic cardiomyopathy and CHF. Diabetes mellitus develops in ~10% of patients.
What enzyme is deficient in xeroderma pigmentosum?
It is characterized by defects in nucleotide excision repair (deficiency in UV-specific endonuclease).
What is the sequence of base excision repair?
Glycosylase cleaves the altered base leaving an empty sugar-phosphate site (apurinic/apyrimidinic [AP] site) → endonucleases cleaves the 5’ end → lyase cleaves the 3’ sugar-phosphate → DNA polymerase fills in the gap → ligase seals the nick
What inheritance pattern does spina bifida demonstrate?
Multifactorial - neural tube defects are more common in first-degree relatives of those affected, with a recurrence risk of 2%-5%.
Other multifactorial diseases include cleft lip and palate, diabetes mellitus, coronary artery disease, and hypertension.
Why is huntington gene expression decreased in Huntington Disease?
The CAG trinucleotide repeat leads to increased histone deacetylation, thus causing transcriptional repression (silencing)
What is porphyria cutanea tarda (PCT)?
A defect in a late step in porphyrin (e.g. heme) synthesis. Most commonly due to a deficiency of uroporghyrinogen decarboxylase (UROD), but can also be caused by deficiencies in coproporphyrinogen oxidase, protoporphyrinogen oxidase, or ferrochelatase. More commonly it is acquired than inherited (acquired in setting of alcohol, smoking, halogenated hydrocarbons, hepatitis C, and HIV). It causes photosensitivity (blisters and vesicles in sites of sun exposure).
Note that early steps in porphyrin synthesis cause abdominal pain and neuropsychiatric manifestations rather than photosensitivity (e.g. ALA dehydratase).
