Basic Medical Sciences for MRCP Part 1

441 Pages·2005·14.05 MB·English

by  Philippa J. Easterbrook

Preface

Both MRCP (UK) parts 1 and 2 examinations require a sound knowledge and
understanding of the basic sciences. This concise but comprehensive revision
guide summarizes the core basic sciences relevant to the MRCP examination in
eight chapters: Genetics and molecular medicine, Microbiology, Immunology,
Anatomy, Physiology, Biochemistry, Cell biology and clinical chemistry,
Statistics and epidemiology, and Clinical pharmacology. It is intended primarily
for MRCP part 1 and 2 candidates, although those studying for other
postgraduate examinations, such as the US Medical Licensing Examination
(MLE) and PLAB, may also find it useful. Information is presented in the form of
lists, tables, flow diagrams and simple illustrations, and each chapter is
prefaced by a summary of the key topics covered to provide a useful
framework for revision of the important concepts and facts. No book of this
length covering such a wide area could hope to be comprehensive, and I have
therefore concentrated on recurring examination themes, topical issues, and
recent developments reported in the scientific and medical literature. When a
particular topic is unfamiliar or a point needs further clarification, one of the
many excellent basic science textbooks should be consulted. A number of
practice Best of Five MCQs in the basic sciences for MRCP are also available.

In this third edition, all chapters have been extensively updated with new

material to reflect recent developments, particularly in molecular medicine,
immunology and microbiology. We have also improved the layout. Topics of
particular relevance are highlighted in shaded boxes; and a second colour has
been used to enhance the clarity of tables and figures.

Acknowledgements
I am grateful to many former colleagues in Oxford, Baltimore and London who
provided vaiuable criticism on earlier editions. Thanks also to the team at
Elsevier in Edinburgh for their project management ar]d to David Gardner for his
skilled art work.

I would appreciate any corrections, clarifications or suggestions for future

editions.

London

The MRCP (UK) Part 1 Examination

PJE

The purpose of the MRCP Part 1 exam is to test the candidates' broad
knowledge and understanding of basic clinical science; their awareness of
important new advances in disease mechanisms; and their ability to apply their
knowledge and problem-solving skills to clinical situations.

The MRCP Part 1 exam consists of two papers, each lasting three hours.
Each paper comprises 100 MCQs in a 'Best of Five' format, where a candidate
must choose one best answer from five possible answers. Each MCQ has a
question stem, which may contain clinical information, followed by five
branches. Candidates are required to select the Qne branch that represents the
best answer to the question. There is no negative marking, and one mark is
awarded for each correct answer. No marks are given for an incorrect answer,
or for answers in excess of the one required. Normal ranges for all laboratory
measurements are quoted in the exam paper.

The general composition of the paper by topic and speciality is as follows:

Basic and clinical science questions comprise at least 25% of the paper with
25 questions

Cell, molecular and membrane biology
2

Clinical anatomy
3

Clinical biochemistry and metabolism
4

Clinical physiology
4
Genetics
3

Immunology
4
Statistics, epidemiology and evidence-based medicine
5

Clinical pharmacology, therapeutics and toxicology account for 15 questions

Clinical specialities account for 60 questions, but many of these questions also
test knowledge of underlying scientific principles.

Cardiology
Gastroenterology and hepatology
Clinical haematology and oncology
Infectious and sexually transmitted diseases
Endocrinology
Nephrology
Neurology
Respiratory medicine
Rheumatology
Psychiatry
Dermatology
Ophthalmology

15
15
15
15
15
8
15
15
15
15
8
4

Questions in each speciality are randomized across both papers. Further details
on the exam are available from www.mrcpuk.org/mrcppt.

Contents

1 GENETICS AND MOLECULAR MEDICINE
1

2 MICROBIOLOGY
39

3 IMMUNOLOGY
87
4 ANATOMY
133

5 PHYSIOLOGY
179
6 BIOCHEMISTRY, CELL BIOLOGY AND

CLINICAL CHEMISTRY
239

7 STATISTICS AND EPIDEMIOLOGY
305

8 CLINICAL PHARMACOLOGY
337

INDEX
415

GLOSSARY
2

NUCLEIC ACIDS 6
Nucleic acid structure
6
DNA
7
RNA
7
Protein synthesis
8
Genetic code
9

Control of protein synthesis
10
Cell cycle
l1

RECOMBINANT DNA TECHNOLOGY

11

Applications
11
Basic techniques of gene analysis
11
DNA probe hybridization
11
Gene mapping
12
Gene cloning
13
Gene sequencing
14
Polymerase chain reaction
16
Gene therapy
18

CHROMOSOMAL ABNORMALITIES
18

Autosomal disorders
19
Trisomies
19

Deletions
20
Philadelphia chromosome
20
Sex chromosome disorders
20

SINGLE-GENE ABNORMALITIES
22

Autosomal dominant inheritance
22

Autosomal recessive inheritance
23

Sex-linked dominant inheritance
24

Sex-linked recessive inheritance
25

Mitochondrial genetic disorders
26
Dynamic/unstable mutations: triplet or
trinucleotide repeat diseases
27

Molecular basis of single-gene disorders
27
.

PRENATAL AND POSTNATAL
DIAGNOSIS
28

Prenatal: indications
28 ·

Postnatal diagnosis
29

MULTIFACTORIAL OR POLYGENIC
INHERITANCE
29

Population genetics
31

ONCOGENESIS
32
Regulation of gene expression
32
The somatic evolution of cancer
32

Oncogenes
33
Tumour suppressor genes and inherited

family cancer syndromes
34
Mismatch repair genes
35
Apoptosis
35

IMMUNOGENETICS
36
The major histocompatibility complex

36
Classification of diseases associated
with HLA
37

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GLOSSARY

Alleles

Amplification

Aneuploidy

Antisense
technology

Autosome

Barr body

cDNA

Chimera

Chromatids

Chromosome
mapping

Clone

Cloning

Concordant twins

Conserved
sequence

Deletion

Diploid

Discordant twins

Dizygotic twins

Alternative forms of a gene found at the same locus on
a particular chromosome.

(i) Treatment designed to increase the proportion of
plasmid DNA relative to that of bacterial DNA.
(ii) Replication of a gene library in bulk. (See polymerase
chain reaction, p. 16.)

A chromosome profile with fewer or greater than the
normal diploid number: e.g. 45 (Turner's syndrome) or
47 (Down's syndrome) chromosomes.

Use of synthetic nucleotide sequences, complementary
to specific DNA or RNA sequences, to block expression
of a gene.

Any chromosome other than the sex chromosomes: i.e.
22 pairs in humans.

All X chromosomes in excess of one per cell are
inactivated so that only one is active (Lyon hypothesis),
which is visible in interphase as a dark-staining Barr
body: i.e. no Barr body in male or XO female.

A single-stranded DNA complementary to an RNA,
synthesized from it by the enzyme reverse
transcriptase in vitro; often used as a probe in
chromosome mapping.

An individual composed of two populations of cells from
different genotypes: e.g. blood group chimerism.

Equal halves of a chromosome following replication.

The assigning of a gene or other DNA sequence to a
particular position on a specific chromosome.

A cell line derived by mitosis from a single diploid cell.

The isolation of a particular gene or DNA sequence.
In recombinant technology, genes or DNA sequences
are cloned by inserting them into a bacterium or other
microorganism, which is then selected and propagated.

Members of a pair of twins exhibiting the same trait.
(See also Discordant twins.)

A DNA sequence that has remained virtually unchanged
throughout evolution. This is usually taken to imply that
the sequence has an important function.

A chromosomal aberration in which part of the
chromosome is lost.

T"1e chromosome number of a somatic cell: 1.e. 46 in
h Jmans.

C ly one twin has the trait. (See also Concordant twins.)

fwins produced by two separately fertilized ova: i.e. no
more genetically similar than brothers and sisters. (See
also monozygotic twins.)

DNA fingerprinting
A pattern of DNA sequences, e.g. tandem repeat
sequences, unique to an individual. This DNA profile
can be detected in cells (e.g. blood or semen) and can
be used in criminal cases and paternity suits.

Exon
Portion of the DNA that codes for the final mRNA and is
then translated into protein.
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Expressivity
Variation in the level of expression of a particular gene.
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Gamete
Haploid sperm or egg cell.
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Gene
A region of DNA that encodes a protein.
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Gene therapy
See page 18.

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Genome
The complete set of genes of an organism and the
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intervening DNA sequences. The Human Genome
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Project was an international research programme aimed
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at mapping all the genes in the human genome.
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Genotype
The genetic constitution of an individual, usually at a
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particular locus.
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Haploid
The chromosome number of a normal gamete: i.e. 23 in
~
humans.
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Haplotype
The particular combination of alleles in a defined region
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of a chromosome. Originally used to define the HLA
m
type of an individual, it is now routinely used to describe
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any combination of alleles, such as those used in
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prenatal diagnosis by genetic linkage.
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Heteroploidy
Abnormal appearance of the karyotype due to alteration
in (i) the number of chromosomes or (ii) their shape and
form.

Homologous
The two matching members of a pair of chromosomes.
chromosomes

Hybridization
The joining of the complementary sequences of DNA (or
DNA and RNA) by base pairing.

Index case
See Proband.

In situ
Use of a labelled probe to detect any complementary

hybridization
DNA or RNA sequence in a tissue section, cultured cell
or cloned bacterial cell.

lntron
Intervening sequence on DNA that does not appear in
the final RNA transcript.

Karyotype
The presentation of a cellular chromosome profile.
Normal human karyotype is 44 autosomes and two sex
chromosomes - XX female, XY male.

Library
A collection of DNA clones representing either all
expressed genes i.e. a cDNA library, or a whole genome
i.e. a genomic library.

Linkage
The association of two linked alleles more frequently

disequilibrium
than would be expected by chance.

Linkage map
A map of the relative positions of g ne loci on a
chromosome, deduced from the frequency with which
they are inherited together.
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Locus

Meiosis

Site of a gene on a chromosome.

Sex cell division or reduction division. Formation of
gametes with half the number of chromosomes
(haploid) as the parent cell (diploid): i.e. 23.

Mitosis
Somatic cell division: each daughter cell has the same
complement of chromosomes as the parent: i.e. 46.

Monozygotic twins
Twins produced from a single fertilized ovum. (See also
Dizygotic twins.)

Mosaic
An individual with abnormal genotypic or phenotypic
variation from cell to cell within the same tissue.

Non-disjunction
The failure of two members of a chromosome to
separate during cell division, so that both pass to the
same daughter cell.

Northern blotting
See page 13.

Oncogenes
Genes of either viral or mammalian origin that cause
transformation of cells in culture. In normal cells, they
are 'switched-off' or downregulated. They have copies
in both viruses (v-onc) and mammalian cells (c-onc or·
protooncogenes) and have products that are essential
to normal cell function or development.- These include
proteins (guanine-nucleotide binding proteins), cell
surface receptors (epidermal growth factor receptor),
and cellular growth factors (platelet-derived growth
factor).

Penetrance
The proportion of individuals with a given genotype
(usually a disease-causing mutation) manifesting a
phenotype (usually a disease).

Phage

Phenotype

Physical mapping

Plasmid

Pleiotropy ·

Polymerase chain
reaction

Polymorphism

Virus that multiplies in bacteria.

The characteristics of an organism which result from an
interaction between gene (the genotype) and
environment.

A linear map of the location of genes on a chromosome,
as determined by the physical detection of overlaps
between cloned DNA fragments rather than by linkage
analysis.

An autonomously replicating ONA element, separate
from the chromosome. These units, which only occur in
bacteria, can be used as vectors of small fragments of
foreign DNA.
·

The production of multiple effects by a single gene.

See page 16.

The occurrence in one population of two or more
genetically determined forms (alleles), al.I of which are
too frequent to be ascribed to mutation: e.g. blood
group systems, the HLA system and various forms of
G6PDH deficiency.

Polyploidy

Primer
(oligonucleotide
primer)

Proband or
propositus

Probe

Protooncogene

Reporter gene

Restriction
endonuclease

Restriction
fragment length
polymorphism
(RFLP)

Reverse
transcription

Southern blotting

Splicing

Tandem repeat
sequences

Tetraploid

Transfection

Trans location

Transposition

Transposon

Triploid

Trisomy

Tumour
suppressor gene
(antioncogene)

Homologous chromosome numbers in more than two
complete sets: i.e. three sets: triploid or 69
chromosomes; four sets: tetraploid or 92 chromosomes.

A short DNA sequence used to initiate the synthesis of
DNA, as in a polymerase chain reaction.

·The family member who first presents with a given trait.

A specific DNA sequence, radioactively or fluorescently
labelled, used with hybridization techniques to detect
complementary sequences in a sample of genetic
material.

See page 33.

A gene whose product can be used as a genetic 'label'.
For example, a gene for neomycin resistance
incorporated into a plasmid before transfection allows
the detection of successfully transfected cells.

An enzyme that cleaves DNA at a specific site.

See page 13.

DNA synthesis from RNA templates, catalysed by the
enzyme reverse transcriptase. It is used to synthesize
DNA for probes and occurs naturally in retroviruses.

See page 13.

The removal of introns from messenger RNA and the
joining together of adjacent exons.

Multiple copies of a short DNA sequence lying in a
series along a chromosome; used in physical mapping,
linkage mapping and also in DNA fingerprinting because
each person's pattern of tandem repeats is likely to be
unique.

See Polyploidy.

The transfer of new genetic material into cells.

The transfer of genetic material from one chromosome
to another non-homologous chromosome.

Movement from one site in the genome to another.

A segment of DNA that can move from one position in
the genome to another.

See Polyploidy.

The presence of an extra chromosome, rather than the
usual diploid set: i.e. 47 in humans.

See page 34.

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Vector
A DNA molecule, usually derived from a virus or
bacterial plasmid, which acts as a vehicle to introduce
foreign DNA into host cells for cloning, and then to
recover it.

Zygote
Fertilized egg.

NUCLEIC ACID STRUCTURE

All nucleic acids are polynucleotides. A nucleotide consists of three
components (Fig. 1.1 ):
1. A base
2. A pentose sugar
3. 1-3 phosphate groups.
There are two kinds of nucleic acids (Table 1.1 ):
• Deoxyribonucleic acid (DNA)
• Ribonucleic acid (RNA).

Hydrogen bonds

(not corent) _/l

Base
Base~

Base

Fig. 1.1 Nucleotide structure.

Table 1.1 Structure of nucleic acids

Nucleic acid
Sugar
Bases
Monomeric unit•

Purinest
Pyrimidines

DNA
2' Deoxyribose
Adenine (A)
Thymidine (T)
Deoxyribonucleotides.

Guanine (G)
Cytosine (C)
e.g. adenylic acid (AMP),
thymidylic acid (TMP)

RNA
Ribose
Adenine (A)
Uracil (U)
Ribonucleotides, e.g.

Guanine (G)
Cytosine (C)
adenylic acid (AMP).
uridylic acid (UMP)

·11 the sugar is not phosphorylated, the structure is called a nucleoside.
1Xanthine and hypoxanthine are also purines.

Table 1.2 Proportions of different types of nuclear DNA

Type of DNA
Percentage of total ONA

1. Single copy
70

2. Repetitive DNA
30

(a) Tandem repeats
(10)

Microsatellites
Minisatellites
Macrosatellites

(b) Interspersed repeats
(20)

Short interspersed repeats (SINES)
Long interspersed repeats (LINES)

DNA (Tables 1.1 and 1 .2)
• Double-stranded, double helix. Found primarily in the chromosomes of the

cell nucleus.

• Two polynucleotide chains are antiparallel (i.e. one chain runs in a 5' to 3'

direction; the other runs 3' to 5') and held together by hydrogen bonds
between the bases:

- adenine pairs only with thymidine (2 hydrogen bonds)
- guanine pairs onlX with cytosine (3 hydrogen bonds).
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• In each diploid cell double-stranded DNA is distributed between 23 pairs of

chromosomes, comprising about 3.5 x 109 base pairs.

• Approximately 90% of the cell's DNA exists as a nucleoprotein called chromatin.

Chromatin is comprised of DNA and both histone and non-histone proteins.

Mitochondrial DNA (mtDNA) (see also p. 26)
• Mitochondria contain their own DNA which differs from that of the rest of the

cell.
• Codes for: 22 tRNAs

Satellite DNA

2 mt rRNAs
3 proteins, which are all subunits of the oxidative phosphorylation
pathway.

• Highly repetitive DNA which comprises approximately 25% of the genome.

Some sequences have no known function.

• Subsets of satellites can be classified according to their sequence motifs,

length and size into:
1. Satellite DNA (5-200 base pairs)
2. Minisatellite DNA: Hypervariable family (10- 60 base pairs), and Telomeric

family (6 base pairs).

3. Microsatellite DNA (1-4 base pairs).

RNA (Table 1.1 l
• Single-stranded; 90% is present in the cell cytoplasm and 10% in the

nucleolus.
• Three forms:

1. Messenger RNA (mRNA) is the template for polypeptide synthesis. It has
a cap at the 5' end, and a poly A tail at the 3' end (Fig. 1.2).
2. Transfer RNA (tRNA) brings activated amino acids into position along the

mRNA template. It forms a cloverleaf structure that contains many unusual
nucleotides.
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Leader sequence

Methylated

cap

Initiation

sequence (AUG)

Fig. 1.2 Messenger RNA.

Coding
region

3'

Trailer

sequence

·A- A- A- A- A-A
~

Poly-A
tail

3. Ribosomal RNA (rRNA) is a component of ribosomes which functions as
a non-specific site of polypeptide synthesis. In eukaryotic cells there are
four rRNA molecules of 18, 28, 5 and 5.8s.

PROTEIN SYNTHESIS (Fig. 1.3)

~~
C

e plication)

DNA ----- RNA ---- Polypeptide ----- Protein
chain
Transcription
@)

Translation

@)

Fig. 1.3 Protein synthesis.

1. DNA replication (Fig. 1.4)

Post-translational

modification

• Replication is semiconservative, i.e. each daughter molecule receives one
strand from the parent DNA molecule.
• Unwinding proteins, DNA-directed RNA polymerase, DNA polymerase and
ligase are also required.

• DNA polymerases synthesize the new strand in a 5' to 3' direction. They are

the enzymes responsible for DNA chain synthesis. Four have been identified:
a, p, y and&.
• Discontinuous replication, i.e. one or both DNA strands may be synthesized
in pieces known as Okazaki fragments, which are then linked together to
yield a continuous DNA chain.

2. Transcription
• Synthesis of complete RNA molecules from DNA.
• Takes place in the nucleus. One of the two DNA strands acts as a template

for the formation of an mRNA molecule with a complementary base
sequence.

5'~3~

3

)
Daughter strands

l
~

~5~

Fig. 1 .4 DNA replication.

• Transcription yields three types of RNA: mR1,,.A, tRNA and rRNA.
• Fully conservative replication.
• Synthesis in ~' ---+ 3' direction.
• Controlled by the interaction between specific DNA sequence motifs
(cis elements) and DNA-binding proteins (transactivating factors).

• DNA-dependent RNA polymerase is required to recognize and bind to
sequences called promoters (located upstream of transcription start site) to
initiate transcription. RNA polymerase must also cooperate with other proteins
(transcription factors) which control transcription, together with specific
enhancers or repressors, to form an initiation complex (see Note below).

• Processing: the RNA must be further modified to make it functionally active,
e.g. non-coding intrans (i.e. 'junk' sequences) cut out, intervening exons
(i.e. coding sequences) spliced or joined together, and in some cases
polyadenylation before delivery of mRNA to the cytoplasm. The process of
gene splicing occurs in the nucleus by means of an RNA-protein complex
called the splicesome. These consist of a core structure made up of 3
subunits called small nuclear ribonuclear proteins (sn-RNPs pronounced
'snarps') and non-sn-RNP splicing factors. Antibodies against these
ribonucleoproteins are found in patients with SLE.

Note: Unlike DNA polymerase, RNA polymerase can initiate the synthesis of
new strands: There are 3 types of chromosomally encoded RNA polymerase
(I, II and 111), which recognize different types of RNA molecule. The RNA of an
RNA virus is replicated by an RNA-dependent RNA polymerase. Oncogenic
RNA viruses synthesize DNA from RNA, and insert the DNA into the
chromosomes of animal cells. This reverse transcription is mediated by an
RNA-directed DNA polymerase (reverse transcriptase).

3. Translation
• Protein synthesis according to the amino acid code in mRNA.
• Takes place in cytoplasm.
• Occurs on ribosorrtes when a tRNA molecule with three bases (anticodons)
specific for a particular amino acid binds to the complementary mRNA codon.

• Four stages:

1. Amino acid activation.
2. Initiation of polypeptide chain formation begins with the amino acid,
methionine.
3. Chain elongation.
4. Chain termination. Three codons, UAA, UGA and UAG, are signals for
chain termination.

4. Post-translational modification ·of proteins
• Gives the mature protein functional activity and includes peptide cleavage
and covalent modifications, such as glycosylation, phosphorylation,
carboxylation and hydroxylation of specific residues.

• A newly synthesized protein is directed to appropriate destination, e.g.

cytoplasm or cell membrane, by conserved amino acid sequence motifs,
e.g. the signal peptide, and moieties added by post-translational modification.

GENETIC CODE

• Each DNA strand codes for the synthesis of many polypeptides. A segment
of DNA that codes for one polypeptide chain is called a gene.
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• Genetic information is encoded by a sequence of bases in a non-overlapping
code. Three bases (a triplet) specify one amino acid. There are 43 , or 64,
possible trinucleotide sequences of the four nucleotides in mRNA.

• The genetic code is degenerate, i.e. some amino acids are coded for by more
than one triplet codon. AUG is the codon for chain initiation and for the
amino acid methionine.

• Coding sequences (exons) are interrupted by sequences of unknown function
(intrans).

• Single base or point mutations may involve base transitions, transversion,

deletion or insertion.

CONTROL OF PROTEIN SYNTHESIS

In eukaryotes, this may occur by modification of DNA, or at the level of
transcription and translation.
1 . Regulation by induction-derepression
2. Regulation by repression.

Possible faults in protein biosynthesis (Fig. 1.s)

Gene
I I .• I • I

Transcription
i
I Initial mRNA I I • I .,

mRNA
i
processing

I Final mRNA

Translation
i

I Initial protein
000

Post-translational
i
processing

I Final protein
0

Transport to correct
i

location and 30
structure

Functional protein
0

Fig. 1.5 Faults in protein synthesis.

I

I

AAA

Possible faults in protein blosynthesis /

Gene deletion (partial or complete)

Defective regulation
(promotor mutants)

Altered splice site sequence
Abnormal new splice site
Partial gene deletion

Polyadenylation mutants

Premature stop codon

Altered amino acid sequence

Altered amino acid sequence
(point substitution or frameshift)

Inhibitors of protein synthesis
Antibiotics
Rifampicin, streptomycin, tetracycline, chloramphenicol,

erythromycin.
Pyrimidine analogues
5-Fluorouracil, cytosine arabinoside, idoxuridine.

Purine analogues
Mercaptopurine, adenine arabinoside, thioguanine.

Alkylating agents
Cyclophosphamide, chlorambucil, bleomycin.

0

Others
Vincristine, bleomycin, methotrexate, doxorubicin, etoposide, hydroxyurea,

cisplatin.

CELL CYCLE (see p. 242)

• Replication of DNA occurs during the S phase of the cell cycle (i.e. DNA

synthetic phase). This is preceded by G1 (the first gap phase), when the cells
prepare to. duplicate their chromosomes. After the S phase, there is a second
gap phase (G2), during which cells prepare to divide. Cell division occurs
during the mitotic (M) phase.

RECOMBINANT DNA TECHNOLOGY

APPLICATIONS (Fig. 1.6)

Study of gene structure
and function

Source tissue

mRNA
•
cDNA •
r

DNA
+

Restriction
fragments

81osynthesis

t t

Cloned in
eg. insulin.
~
vector
growth hormone

Nucleotide~ + ~
+

sequence
• r-- Probe ~
~Gene insertion in

t

J
f
f
replicating cells

f
Test for homology
Linkage with fragment
I

by hybridization
polymorphism
f
Amino acid
sequence

t +

Protein structure
and function

Antenatal diagnosis
or carrier detection

Fig. 1.6 Applications of gene analysis.

Transformed

cells

+

Gene therapy
for genetic disease

Modified from Emery's elements of medical genetics, 10th edn. Churchill Livingstone.

BASIC TECHNIQUES OF GENE ANALYSIS

DNA can be extracted using standard techniques from any tissue containing
nucleated cells, including blood and chorionic villus material.

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