Robbins 7th ed - Chapter 5 - Genetic Disorders (3)

Question 1

What is a conservative missense mutation, and what is a non-conservative missense mutation?

Answer 1

A conservative missense mutation is when there is a point mutation, which results in a single amino acid difference, but this has little or no effect on the function of the resulting protein. A non-conservative missense mutation is when the substitute amino acid is biochemically different to the original, producing an altered function in the protein produced (e.g. sickle cell anaemia).

Question 2

What is the Mendelian inheritance of Marfan syndrome?

Answer 2

Autosomal dominant.

Question 3

What is the defective protein in Marfan syndrome?

Answer 3

Fibrillin-1, which is a major component of microfibrils of the extracellular matrix, particularly in the aorta and ligaments.

Question 4

Name some clinical features of Marfan syndrome.

Answer 4

Tall stature, long fingers, bilateral subluxation of lens in eye, cardiac valvular malformations, aortic aneurysm.

Question 5

What is Ehlers-Danlos Syndrome?

Answer 5

There are multiple different Ehlers-Danlos syndromes, each affecting different genes, and each affecting collagen synthesis in a different way.

Question 6

What is a characteristic feature of most of the Ehlers-Danlos syndromes?

Answer 6

Hypermobility and a predisposition to joint dislocation, due to a lack of collagen-supported connective tissue. Fragile skin and poor wound healing, due to lack of tensile strength.

Question 7

Where is most of the body’s LDL metabolised? How does this happen?

Answer 7

70% occurs in the liver. LDL binds to LDL receptors on hepatocytes, which triggers endocytosis and fusion with lysosomes for enzymatic degradation.

Question 8

Describe how the presence of cholesterol will regulate cellular accumulation of cholesterol.

Answer 8

1 – It inhibits HMG CoA reductase, which is an enzyme involved in synethesizing cholesterol
2 – It activates a process favouring storage of cholesterol
3 – It suppresses the synthesis of LDL receptors, protecting the cell from excessive accumulation of cholesterol.

Question 9

What is the genetic defect in familial hypercholesterolaemia? What is the result of this? What is the Mendelian inheritance?

Answer 9

Mutations in the gene encoding LDL receptor, leading to defective clearance of LDL, and higher circulating levels of LDL. It is an autosomal dominant disorder.

Question 10

Name two lysosomal storage diseases, caused by inherited genetic mutations.

Answer 10

Tay-Sachs disease – gangliosides accumulate in the CNS, causing severe CNS defects and death at age 2-3yo.
Gaucher disease – accumulation of glucocerebroside

Question 11

What is meant by the term “euploidy”? And what is aneuploidy?

Answer 11

In humans, this is when the number of chromosomes inside a cell is an exact multiple of 23 (the haploid number). Aneupoloidy is when it is not an exact multiple of 23.

Question 12

What is a robertsonian translocation?

Answer 12

This is when there is a translocation of the long arm of chromosome 21 onto another chromosome (e.g. 22 or 14). An ovum with a robertsonian translocation can produce a fetus with Down Syndrome.

Question 13

What is a Barr body?

Answer 13

This is the inactivated X-chromosome in a female cell. Remember that at day 5.5 of embryogenesis, each of the cells undergo inactivation of one X-chromosome at random, resulting in mosaicism.

Question 14

True or False: During X-inactivation, all the genes on the X-chromosome become inactivated.

Answer 14

False. This is exemplified in Turner’s syndrome, because some X-linked genes require both copies for normal expression. Also, inactivated X-chromosomes (Barr bodies) are reactivated during oogenesis.

Question 15

What is the fertility of a male with Kleinfelter syndrome?

Answer 15

There is reduced spermatogenesis, and there is male infertility. Hypogonadism is the main feature of Kleinfelter syndrome.

Question 16

Describe the different chromosomal profiles that are possible in Turner’s syndrome.

Answer 16

Approximately 57% are missing an entire X chromosome. 29% are mosaics, meaning that different cells have different chromosome numbers: some XX, some XO, some XXX, some XY. 14% have structural abnormalities of the X chromosomes (e.g. loss of the short arm)

Question 17

In basic terms, describe the abnormal feature of the X-chromosome in the Fragile X syndromes.

Answer 17

Fragile X involves a trinucleotide repeat on an X-chromosome.

Question 18

What is genomic imprinting?

Answer 18

This is an epigenetic process whereby either the maternal allele or the paternal allele is silenced. It occurs in the ovum or sperm, before fertilization. This occurs on between 200 and 600 genes.

Question 19

What is interesting about the relationship between Prader-Willi syndrome and Angelmann syndrome?

Answer 19

Prader-Willi is (most often) due to a deletion from the paternally-derived chromosome 15. Angelmann is due to a deletion at the same chromosomal region, but from the maternally-derived chromosome 15.

Question 20

What are the clinical features of Prader-Willi ? And Angelmann syndrome?

Answer 20

Both are mentally retarded. Prader-Willi patients have short stature, obesity and hypotonia. Angelmann patients are described as “happy puppets”, with ataxia and inappropriate laughter.

Question 21

Give a basic explanation for how FISH works?

Answer 21

Fluorescent in Situ Hybridisation uses artificial DNA sequences (produced in bacteria) that are labelled with a fluorescent dye. It is applied to non-dividing cells (in interphase) that are pre-treated so as to “melt” the DNA, allowing the probe to hybridize to its homologous sequence and the fluorescent label can be visualized under the microscope.