Diseases Flashcards
Thalassemias:
β- An inherited anemia due to deficient production of β-globin protein by erythroid cells. Can
occur due to different types of mutations- one of which can occur in the β-globin promoter- reducing
the amount of β-globin mRNA and thus protein produced (is usually clinically mild).
γδβ- due to deletion of the locus control region (LCR) of the β-globin gene cluster (the LCR
region is essential for the transcription of all genes within the cluster)
Hemophilia B Leyden
Is an X-linked disorder that affects clotting. Affected males have 1%
of normal factor IX active until puberty due to inherited mutations in a DNA control element in the
promoter of the Factor IX gene (which prevents the binding of the appropriate transcriptional
activators). Alternative transcriptional activators can bind overlapping sites in the promoter, and at
puberty, when the androgen receptor becomes active- it can bind at the promoter site and increase
transcription such that males after puberty make ~60% the normal amount of factor IX.
Fragile X-Syndrome
Affects 1 in ~1500 males and results in mental retardation, dysmorphic
facial features, and postpubertal macroorchidism. CGG repeat in the 5’ region of the FMR1 gene
facilitates methylation of the cytosine residues in CpG islands and transcriptional inactivation of the
FMR1 gene. Normal males have 6-50 or so CGG repeats in this region, however, affected males have
an expansion of this repeat sequence (>200 copies)- leading to increased transcriptional silencing of
the FMR1 gene.
Craniosynostosis
Craniosynostosis is characterized by the premature closure of one or more
sutures in the skull and affects 1/3000 infants. One particular variant of craniosynostosis (Bostontype)
occurs as a result of a mutation in the homeodomain protein MSX2. MSX2 is normally required
for proper craniofacial development by affecting the transcription of a number of genes important in
this process. When the DNA binding domain (or homeodomain) of this protein has a one amino acid
substitution, the protein binds DNA more strongly- giving a “gain of function” or “hypermorphic
allele”. This mutated hyperactive protein then affects the transcription of other genes critical for suture
closure, leading to craniosynostosis.
Androgen insensitivity syndrome (AIS)
Androgen insensitivity syndrome includes
feminization or undermasculinization of the external genitalia at birth, abnormal secondary sexual
development in puberty, and infertility. It occurs in males who are a normal karyotype (46 X,Y), but
have mutations in either the DNA binding domain or the ligand binding domain of the androgen
receptor (a zinc finger DNA binding protein). This makes the patients less responsive to androgens,
leading to the aforementioned characteristics. Depending on the degree to which the mutation disrupts
the function of the androgen receptor- varying levels of AIS can be observed (complete, partial, mild).
Waardenburg Syndrome type II
Is characterized by deafness, pigmentation anomalies of the
eyes, and other pigmentation defects (hair, skin). Mutations in the microphthalmia-associated
transcription factor (MITF) gene (which encodes a bHLH DNA binding protein) are observed in 15-
20% of the patients. This gene encodes a transcription factor that plays a major role in the
development of melanocytes.
Rubinstein-Taybi Syndrome-
A rare genetic multisystem disorder (affects 1/125,000).
Characterized by growth retardation, mental retardation, craniofacial dysmorphism, abnormally broad
thumbs and great toes. Results from mutations in one copy of the CREB binding protein (CBP) gene.
CBP is an essential transcriptional coactivator for many different transcription factors and is a histone
acetyltransferase. It is normally recruited to many genes to activate transcription, and thus
haploinsufficiency can result in widespread transcriptional changes.
Leukemia- A hematopoietic malignancy
Are generally the result of chromosomal
translocations leading to gain of function fusion proteins- some of which involve fusions of
transcriptional regulators with HATs or HDACs, altering the activity of the regulators .
progeric syndromes such as Bloom Syndrome and
Werner’s Syndrome.
Mutations in recQ helicases
Meier-Gorlin syndrome (dwarfism).
Mutations in the pre-replication complex
FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature)
Mutations in DNA polymerase epsilon
Puromycin
is an antibiotic that mimics the “acceptor” 3’ end of a tRNA that is charged with an amino acid.
Puromycin can bind in the ribosome as it is translating and covalently attach to a growing polypeptide chain,
preventing the completion of translation. The Streptomyces species that makes puromycin also makes an
enzyme that inactivates the antibiotic inside the bacteria. This enzyme modifies the part of puromycin that is
involved in covalent attachment to the polypeptide chain, rendering puromycin inactive.
- Doxorubicin:
similar intercalator to Actinomycin D. Interferes with DNA replication
- Etoposide and Camptothecin:
are chemotherapeutics that target topoisomerases that relax DNA supercoiling
(super-twisting of the double-helix). Topoisomerases are necessary during DNA replication to avoid
supercoiling as the double helix is opened up to copy the strands. Topoisomerases must break the DNA
backbone to “relax” supercoiled DNA. Drugs that interfere with this process usually leave DNA breaks that
cannot be repaired.
Cisplatin:
base alkylating agent (see above).
