Exam 5: Birth Defects

Question 1

What are the five cellular processes that constitute development?

Answer 1

1) Transcriptional Regulation
2) Morphogen & Cell-to-Cell Signaling
3) Changes in cell shape and organization
4) Cell Migration
5) Programmed Cell Death

Question 2

What are specific transcription factors in development?

Answer 2

• Specific transcription factors that only function in certain cells at certain times
• E.g. HOX

Question 3

What are general transcription factors in development?

Answer 3

• Unspecific
• Found in thousands of transcriptional complexes
• E.g. CREBP & Rubenstein Taybi Syndrome

Question 4

HOX Transcription Factors

Answer 4

• Falls under the general category of transcriptional regulation
• Specific transcription factor
• Important for patterning along the anterior-posterior axis/ limb development
• Mutation can lead to Synpolydactyly

Question 5

Shh Morphogen

Answer 5

• Falls under the general category of morphogen/ Cell-Cell signaling
• Shh is secreted from the notochord/ neural tube and makes a morphogen gradient that organizes cells in the brain & spinal cord
• Mutations causes midline defects & development of posterior limb elements
• E.g. holoprosencephaly

Question 6

Why does a defect in cholesterol biosynthesis affect development?

Answer 6

• Shh interacts with cholesterol
• Thus, disturbances in cholesterol biosynthesis have an effect on development through Shh
• Statins, cholesterol lowering drugs can have a detrimental effect as well

Question 7

How does a cell change shape & polarity?

Answer 7

• Cells respond to their environment to change shape and polarity
• E.g. Polycystic kidney
• Developing kidney tubule must defect fluid flow to develop properly
• Mutation of Polycystin 1 & 2 make it incapable of sensing that flow
• Causes Polycystic Kidney Disease

Question 8

How is cell migration necessary for development of the cerebral cortex?

Answer 8

• Neuronal stem cells have to migrate from the ventricular side of the neural tube along glial cells to their position int the cortex
• Mutation of LIS1 impairs this orderly process of migration
• Causes Lissencephaly (smooth brain)

Question 9

What are the five processes that require programmed cell death?

Answer 9

1) Development of the heart
2) Separation of individual digits
3) Perforation of the anal and choanal membranes
4) Establishment of the connection between the uterus & vagina
5) Development of the immune system

Question 10

Hermaphordites

Answer 10

Patient that truely has testes and ovaries (very uncommon)

Question 11

Pseudohermaphrodites

Answer 11

Patients have testes or ovaries, but phenotype does not match or represent the genetic sex

Question 12

How does the Y chromosome drive male development?

Answer 12

• We all start as females
• SRY, or Sex Determining Region of the Y chromosome is needed for
• TDF, testes determining factor that induces the androgens
• Androgens needed for the development of male external genitalia

Question 13

Masculinization of female babies

Answer 13

• Congenital Adrenal Hyperplasia (CAH)
• Caused by a defect in 21-hydroxylase involved in cortisol biosynthesis
• No cortisol made, but intermediates are shunted into making androgens

Question 14

Feminization of Male Babies

Answer 14

Problem with:

1) SRY (deletion or translocation)
2) TDF
3) Androgens (steroid 5a-reductase or androgen production/signaling impairment)

Question 15

Holocprosencephaly

Answer 15

• Caused by Shh mutation

- Severely affected brain and face development (midline defect)

Question 16

Smith-Lemli-Opitz Syndrome

Answer 16

• Impairment of Shh signaling secondary to a cholesterol biosynthesis defect
• Also called SLOS

Question 17

Polycystic Kidney Disease

Answer 17

• Mutations is Polycystin 1 & 2
• Kidney is unable to sense fluid flow
• Differentiation does not STOP and the kidney develops numerous cysts

Question 18

Lissencephaly

Answer 18

• Smooth brain/ cerebral cortex is thickened & lacks defined cell layers
• Causes severe mental retardation
• Caused by a mutation in the LIS1 gene, which impairs neuronal cell migration

Question 19

Autoimmune Disease

Answer 19

• Lymphocyte lineage that reacts to self-components are supposed to be destroyed in development by apoptosis
• Failure of this process can result in autoimmune disease

Question 20

Which HOX genes are involved in the development of the distal poles of limbs?

Answer 20

HOX 11-13

Question 21

Morphogen

Answer 21

• Substance that is secreted by cells in one part of the embryo
• E.g. Shh

Question 22

What are the phenotype & genotype if the SRY is deleted from the Y chromosome?

Answer 22

• Genotype= XY

- Phenotype= Female

Question 23

What are the genotype & phenotype if the SRY is translocated to the X-chromosome?

Answer 23

• Genotype= XX

- Phenotype= Male

Question 24

What is the most common cause of female pseudohermaphroditism?

Answer 24

• Congenital Adrenal Hyperplasia
• Defect in 21- Hydroxylase
• Cortisol NOT made, intermediates shunted into the production of androgens

Question 25

What are the three common causes of male pseudohermaphroditsm?

Answer 25

1) Defect in testes development
2) Problem in androgen production by the testes i.e. a defect in steroid 5alpha-reductase
3) Androgen insensitivity syndrome i.e. a deficiency in androgen receptor production or signaling

Question 26

Generally, what is the tumor progenitor model of cancer?

Answer 26

Errors in epigenetic programming of stem cells during development lays the seed for cancer later in life

Question 27

How do errors in epigenetic programming lead to cancer?

Answer 27

• Abnormality in epigenetic programming of stem cells generates a pool of incompletely differentiated cells
• These cells retain some embryonal potential & may develop into a benign tumor
• Additional mutations in tumor suppressor genes/ oncogenes can lead to malignant transformation