L51: Genetics of Birth Defects Flashcards
Name five process that require programmed cell death
Name five process that require programmed cell death
Describe how the Y chromosome drives male development
- In presence of Y-chromosome with presence of SRY and TDF, bipotential gonad will develop into Testes - Testes will secrete androgens, which will lead to development of male external genitalia
Explain how masculinization of female babies (male pseudohermaphroditism) and feminization of male babies (female pseudohermaphroditism) occurs
1.) Masculinization of female babies: normal ovaries, but ambiguous or male genitalia - Congenital adrenal hyperplasia (most common, defect in 21-hydroxylase involved in cortisol biosynthesis results in block in cortisol synthesis with intermediates being shunted into androgen synthesis pathway). As result: females have high levels of androgens and develop ambiguous or male genitalia 2.) Feminization of male babies: failure to develop unambiguous male genitalia - Defect in testes development during embryogenesis - Problem in androgen biosynthesis by testes (eg. Issue with steroid 5 alpha reductase) - Deficiency in androgren receptor production or signaling by target cells (androgen insensitivity)
Explain how a cell changes shape and polarity. Provide example using developing kidney
- In development, cells must respond to environmental clues by changing their shape and polarity, which involves rearranging cytoskeleton and polarizing secretion of proteins to apical or basal surfaces of cell - Kidney: Epithelial cells need to sense fluid flow in kidney tubule. Detection of fluid stream leads to stopping of cell proliferation and correct polarization of cell. This occurs by relocating erb-b2/EGFR to basal surface. In polycystic ovary disease, mutations to two genes polycystin 1 and 2 render a cell incapable of sensing fluid flow. As a result, cell proliferation doesn’t stop, development of polarity doesn’t occur (erb-b2/EGFR) remains on the apical surface and kidney develop cysts.
Describe how absence of Y chromosome drives female development
- In absence of Y-chromosome, bipotential gonad develops into ovaries. - Under ovarian hormonal control, female external genitali develop
Discuss how chromosomal aberrations involving SRY can lead to sex reversal disorders
- SRY gene deletion from Y chromosome, embryo develops into a female with XY karyotype - SRY is translocated to X chromosome, embryo develops into a male with an XX karyotype
Explain the tumor progenitor cell model
- Tumor progenitor cells arise during development due to epigenetic changes and the action of tumor progenitor genes (TPG) - Then follows a Gatekeeper Mutation (GKM) in a tumor suppressor gene (TSM) or oncogene (ONC) to generate a benign tumor - Finally, epigenetic and genetic plasticity help evolve the benign growth into a metastatic, invasive and drug resistant tumor - Crux of matter: errors in epigenetic programming of stem cells in development lays seed(s) for cancer later in life
Explain how cell migration is necessary for the development of the cerebral cortex
- Development of CNS begins from neural tube. Neuronal stem cells on ventricular side of neural tube divide and generate neuronal precursor cells - These precursor cells have to migrate outward from the ventricle along a scaffold of glial cells, which occurs in waves - Mutation / deletion of LIS1 gene interferes with orderly pattern of migration. Result = cerebral cortex is thickened and lacks defined cell layers. Lissencephaly = smooth brain. Individuals suffer from severe mental retardation.
Explain why a defect in cholesterol biosynthesis affects development
- For correct functioning of Shh, the protein must interact with cholesterol. - Disturbances in cholesterol biosynthesis will therefore also have broad impact on development. - Defect = Smith-Lemli-Opitz syndrome, IEM in cholesterol synthesis
Describe the five cellular processes that constitute development
1.) Transcriptional regulation 2.) Morphogen and cell-cell signaling 3.) Changes in cell shape and organization 4.) Cell migration 5.) Programmed cell death
Explain the importance of epigenetic programming for cell differentitation
- During development, stem cells gradually and irreversibly change their potential - Stable changes in gene expression lead to fully differentiated cell, which is accomplished by epigenetic changes (methylation, histone deacetylation)
Name two functions of the Shh morphogen
- Shh gradient secreted from notochord and floorplate of neural tube helps organizing the different cells in brain and spinal chord. Defects leads to midline defects - Shh also secreted from zone of developing limb to induce development of posterior limb elements.
Explain the function of the HOX transcription factors in development
- Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc. - Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes - Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.
Compare hermaphrodites and pseudohermaphrodites
- Hermaphrotides: have both testes and ovaries (rare) - Pseudohermaphrodites: either testes or ovaries, but it doesn’t match their genetic sex.
Compare specific and general transcription factors in development
- One of the means of regulating gene expression during development - GTFs: eg. CREB affects expression of many different genes during development. Defect in CREBP causes Rubinstein-Taybi Syndrome. Condition is characterized by short stature, intellectual disability, distinctive facial features,, broad thumbs and first toes. - Specific TFs: eg. HOX determines patterning along anterior-posterior axis. Late HOX genes are also involved in development of distal pole of limbs. Mutations disturb development of fingers and toes. These are autosomal dominant mutations.
