MTM REVISION LECTURE 2021

Tabitha Lambe

TAL648@student.bham.ac.uk

• The BIMS Pre-Clinical Revision Series is developed and run entirely by senior MBChB students who voluntarily give up their time to teach.

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• Teaching is to the best of tutors’ knowledge fully-factually correct, but please bear in mind that neither the tutor(s), nor BIMS accepts any responsibility for any inaccuracies in the material taught.

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• This teaching session is in no way affiliated with or endorsed by the medical school.

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DISCLAIMER

Pre-clinical Revision Series

Dec 2021

1. Cell structure and protein folding

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2. Cell membrane = phospholipid bilayer, types of transport, Na/K pump, coupled transporters

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3. Mitosis, checkpoints and differentiation

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4. Krebs cycle and gluconeogenesis = NOT DONE IN THIS LECTURE

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5. Meiosis and determination of sex

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MTM OVERVIEW

6. Fertilisation, Implantation and Menstrual cycle

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7. Embryology

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8. Epigenetics = NOT DONE IN THIS LECTURE

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9. Mutations and Types of inheritance

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10. Anatomy = NOT DONE IN THIS LECTURE

CELL STRUCTURE AND PROTEIN FOLDING (L01-02)

• Nucleus = Gene Expression
• Nuclear envelope = phospholipid bilayer (double layer) that surrounds genetic material
• Chromatin = complex of DNA and proteins that forms chromosomes in the nucleus
• Nucleolus = dense structure in the nucleus that assembles ribosome subunits
• Rough endoplasmic reticulum = sight of protein synthesis and folding of the proteins
• Smooth endoplasmic reticulum = synthesis lipids
• Golgi Apparatus = packages and modifies proteins to make things like glycoproteins, etc.
• Peroxisome = transports lipids out of the cell, breaks down long chain fatty acids via oxidation

CELL STRUCTURE

• Cytosol = aqueous component of the cytoplasm, allows things to pass through (signal transduction) and site where reactions take place (glycolysis)
• Lysosome = transport proteins out of the cell
• Centrosome = regulates cell division, main place where cell microtubules are organised
• Extra cellular Matrix – allows cells to move and come together (bind) to form structures
• Microtubules = determine cell shape and allow movement of proteins and organelles
• Microfilaments = serve a role in cytokinesis, movement and changes in cell shape (e.g. actin)
• Cytoskeleton = network of protein filaments and tubules in cytoplasm, gives the cell shape

CELL STRUCTURE

PROTEIN FOLDING

1. Primary Protein = sequence of amino acids in a polypeptide chain

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• Secondary Protein = 3D structure with folding of the polypeptide chain due to formation of HYDROGEN bonds
• Alpha helix = spiral formation with hydrogen bonds between N-H and C=O
• Beta pleated sheets = beta strands connected by a backbone of hydrogen bonds

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• Tertiary Protein = 3D structure with folding due to formation of COVALENT/IONIC/DISULFIDE bonds

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• Quaternary Protein = complex of more than 1 protein (e.g. haemoglobin)

If proteins are misfolded there is the UNFOLDED PROTEIN RESPONSE (UPR)

• Occurs with accumulation of misfolded proteins and ER stress
• Stops protein translation & degrades misfolded proteins
• If this does not occur there would be accumulation of misfolded proteins and cell death
• EXAMPLE = Alzheimer’s disease there is accumulation of Tau protein (insoluble)

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Causes of Misfolding = stress, fever, mutations

WHAT HAPPENS IF THIS IS DONE INCORRECTLY?

CELL MEMBRANE & TRANSPORTERS (L03)

CELL MEMBRANE STRUCTURE

FUNCTION = barrier to keep cell constituents in and unwanted substances out

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STRUCTURE

- Composed of fatty-acid-based lipids and proteins

• Lipids are of 2 types – phospholipids and cholesterol

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PHOSPHOLIPID BILAYER

• Have hydrophilic head (attracted to water)
• Have hydrophobic tail (repelled by water)
• Creates a fluid membrane

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CHOLESTEROL

• Rigid ring structure
• At body temp (37) functions to reduce fluidity

TYPES OF TRANSPORT

PASSIVE DIFFUSION

• Moves small uncharged molecules down concentration gradient
• NO energy

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FACILITATED DIFFUSION

- Protein channels = non-directional, fast, non-selective

• Uniporter carrier proteins = highly selective, slow

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ACTIVE TRANSPORT

• Moves molecules AGAINST concentration gradient (
• Requires energy (ATP)

SODIUM/POTASSIUM PUMP

Is a carrier protein that uses ENERGY (ATP) to move molecules AGAINST concentration gradient

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1. 3 Na+ bind to catalytic subunit inside the cell
2. ATPase is activated
3. ATP hydrolyses to produce ADP and a phosphate which attaches to the pump
4. Phosphorylation of subunit causes a conformational change
5. This causes 3 Na+ to be released on exterior of cell and 2 K+ to bind
6. Binding of K+ causes dephosphorylation of pump
7. Pump reverts to original shape
8. 2 K+ ions are released on the inside of the cell

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COUPLED TRANSPORTERS

DEFINITION = transport 2 molecules at same time with at least 1 going AGAINST concentration gradient

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SYMPORT

• Moves solutes in SAME direction
• E.g. sodium/glucose pump

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ANTIPORT

• Moves solutes in DIFFERENT directions
• E.g. sodium/calcium pump (cardiac muscle cells)

MITOSIS & CHECKPOINTS (L04)�DIFFERENTIATION (L05)

PHASES OF MITOSIS

PRE-MITOSIS (INTERPHASE)

• G1 phase = growth and preparation for DNA replication
• S phase = DNA replication
• G2 phase = growth of all other organelles
• M phase = mitosis

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MITOSIS (Pee on the MAT)

• Prophase =
• Metaphase
• Anaphase
• Telophase

Chromosomes start to condense

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Mitotic spindle beings to form

• Spindle is structure made of microtubules
• Function = organise and move chromosomes during mitosis

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Nucleolus disappears = sign that nucleus is ready to break down

EARLY PROPHASE

Mitotic spindle captures and organises chromosomes

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Chromosomes become condensed (compacted)

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Nuclear envelop breaks down releasing chromosomes

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Mitotic spindle grows – microtubules bind to chromosomes at the kinetochore

LATE PROPHASE

METAPHASE

Spindle catches chromosomes and lines them up in centre of cell, ready to divide

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2 kinetochores of each chromosomes are attached to microtubules from opposite spindle poles

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Spindle checkpoint = checks kinetochore is attached to microtubule

- If not cell cycle is suspended

ANAPHASE

Sister chromatids separate and are pulled to opposite ends of cell

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Each sister chromatid is now 2 separate chromosomes

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Cell starts to elongate – preparing for split

TELOPHASE

Cytokinesis (division of cell) takes place

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Mitotic spindle breaks down

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2 new nuclei form for each set of chromosomes

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Chromosomes decondense

MITOSIS CHECKPOINTS

Are critical control points in cell cycle

• Proliferation only occurs when everything falls into place
• Ensures cells divide correctly

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Consequences of Checkpoint Failure

1. Proliferation of cells in absence of growth factor (CANCER)
2. Replication of damaged DNA
3. Splitting of incompletely replicated chromosomes
4. Division of cells with wrong number of chromosomes

CYCLIN DEPENDENT KINASES

These are ENZYMES that regulate the cell cycle

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When activated by growth factors, cyclin levels increase and bind to kinases

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Cyclin levels ACCUMULATE throughout mitosis

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Once levels are high enough they form mature CDKs (M-CDKs)

• M-CDKs then function to phosphorylate (activate) key proteins in mitosis

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GROWTH FACTOR SIGNALLING PATHWAY

1. Growth factor acts on cell

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• Binds to receptor causing phosphorylation to activate it

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• Receptor activates RAS protein

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• RAS protein actives kinase cascade (accumulation)

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• Accumulation of CKDs activates gene regulatory proteins in the nucleus activating proliferation

G1 CHECKPOINT

Ensures cell is large enough to divide

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Regulated by pRB (tumour suppressor protein)

• In absence of growth factors pRB binds to transcription regulator to prevent cell proliferation
• Growth factors act to phosphorylate pRB causing it to release and proliferation to continue

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Tumour Suppressor Proteins

• Prevent proliferation
• If absent or act incorrectly then uncontrolled proliferation can occur (CANCER)

DNA DAMAGE CHECKPOINT

Occurs between G1/S phase

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Any damage to DNA causes increase in p53

• P53 checks DNA for damage and can repair if damage is small
• If damage to severe p53 induces apoptosis

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Increase in p53 causes activation of p21

• P21 is an inhibitor of CDKs so prevents proliferation to give time for DNA repair

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DIFFERENTIATION

STEM CELLS are pluripotent = can differentiation into any cell

• Some remain for maintenance
• Some slightly differentiate to become progenitor cells

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PROGENITOR cells are multipotent = restricted differentiation dependent on location

• Undergo cell division/differentiation known as expansion
• Become terminally differentiated cells

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TERMINALLY DIFFERENTIATED CELLS are unipotent = can only become 1 cell type

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REGULATING DIFFERENTIATION

Regulated by transcription factors and growth factors

• Transcription factors bind to genes to promote or inhibit their transcription
• Genes are only transcribed & translated to protein when transcription factors are activated

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Environment/location of cells is important

• Different cytokines/molecules are released in different locations
• These trigger cell to start differentiation into end product

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MEIOSIS & DETERMINATION OF SEX (L08)

MEIOSIS

FUNCTION = to produce gametes (sperm and egg cells)

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Division process that goes from a diploid cell (2 sets of chromosomes) to a haploid cell (single set of chromosomes)

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Phases of Mitosis

1. Meiosis I = pairs of chromosomes separate
2. Meiosis II = sister chromatids separate

MEIOSIS I

Cell goes through interphase (G1/S/G2)

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During prophase the chromosomes condense but also pair up

• Each chromosome aligns with its partner
• Orientation of each pair is random
• Crossing over of genetic material can occur here

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During anaphase the chromsomes are pulled to opposite ends

• Sister chromatids stay together

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Cytokinesis then occurs to form 2 daughter cells

• These are NON-IDENTICAL

MEIOSIS II

Cells then move to Meiosis II without copying DNA

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Meiosis II is shorter and simpler than Meiosis I

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Sister chromatids separate making haploid cells with DIFFERENT chromosomes

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How Genes are Mixed

1. Crossing over
2. Random orientation of homologue pairs

MITOSIS VS MEIOSIS

MITOSIS

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Results in 2 genetically identical diploid daughter cells

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No crossing over

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During anaphase sister chromatids are separated to opposite poles

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MEIOSIS

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Results in 4 genetically different haploid daughter cells

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Crossing over of genetic material occurs

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During anaphase I sister chromatids are moved together to same pole then in anaphase II separated to opposite poles

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MEIOSIS IN MALES VS FEMALES

MALES

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Germ cells do not enter meiosis until PUBERTY

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Meiosis I and II occur in fast succession

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1 germ cell produces 4 sperm cells

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FEMALES

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Germ cells enter meiosis I during foetal development then stop

• Stops at prophase I

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At puberty a few eggs at a time continue Meiosis I until metaphase II

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Meiosis then finishes upon fertilisation

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1 germ cell produces 1 egg cell

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DETERMINATION OF SEX

Chromosomes in Somatic Cells

• 22 pairs and 1 pair of sex chromosomes
• Female sex chromosomes = XX
• Male sex chromosomes = XY

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Chromosomes in Gametes

• Egg = 22 singular chromosomes and 1 X chromosomes
• Sperm = 22 singular chromosomes and EITHER 1 X or 1 Y chromosomes

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It is therefore the sperm cell that determines sex

FERTILISATION & IMPLANTATION (L08-10)

STRUCTURE OF EGG

CUMMULUS CELLS = outer layer that nourishes and supports egg during development

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ZONA PELLUCIDA = jelly-like basement membrane that protects egg and acts as barrier to sperm

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OOCYTE PLASMA MEMBRANE = contains receptors for sperm binding

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OOPLASMA = cytoplasm of egg cell

STRUCTURE OF SPERM

SPERM HEAD = contains nucleus of chromosomes and receptors to bind to egg

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ACROSOME = contains enzymes release to get through zona pellucida of egg (acrosome reaction)

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MID-PIECE = contains mitochondria to provide energy

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TAIL/FLAGELLUM = use to motor sperm

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AXONEME = central strand of tail

FERTILISATION

1. PENETRATION OF CUMULUS CELLS
• Sperm releases hyaluronidase (enzyme) which breaks down cumulus cells

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2. ACROSOME REACTION

• Sperm binds to zona pellucida
• Triggers acrosome to swell and fuse with the sperm cell membrane (exocytosis)
• Acrosome bursts and releases proteolytic enzymes which digest zona pellucida

FERTILISATION

3. PENETRATION OF PLASMA MEMBRANE

• Sperm binds to receptors on oocyte plasma membrane (Izumo-Juno)
• Causes fusion of sperm and egg membranes
• Sperm nucleus enters egg cytoplasm

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4. BLOCK TO POLYSPERMY

• 1^st sperm makes contact with egg
• Release signal that causes egg to release substance
• This causes cross links to form between zona pellucida so no more sperm can pass through
• Receptors on egg cell are internalised
• Prevents double fertilisation

FERTILISATION

5. FUSION OF NUCLEI

• Female and male pronuclei breakdown
• 2 sets of chromosomes mix together to produce diploid zygote

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6. 1^st MITOTIC DIVISION

• Occurs immediately
• During completion there is formation of a small haploid cell pushed to outside of cell called polar body
• Polar body = acts as nutrients for developing zygote and later undergoes apoptosis

PATHWAY OF EGG

Egg is released from ovary into fallopian tube during OVULATION

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Moves down fallopian tube and enters uterus at around day 4-5

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Implants into the uterine wall at around day 8-9

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During its path it continues to divide

ZYGOTE DEVELOPMENT

As it moves it continues to divide via mitosis

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Doubles in size with each division – e.g. 2-cell, 4-cell, 8-cell, morula, blastocyst

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MORULA = ball of cells loosely held together

• If you were to separate cells at this stage every cell could form a separate individual

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BLASTOCYST = specialisation into 2 cell types

2. Inner cell mass (embryoblast) = gives rise to embryo
3. Trophoblasts = outer layer that forms placenta

IMPLANTATION

STAGE 1

• Blastocyst makes contact with receptors in endometrium (uterus)

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STAGE 2

• Trophoblasts differentiate into 2 layers
• Syncitiotrophoblasts = lose cell membrane and fuse to form a cytoplasm called syncytium
• Cytotrophoblasts = remain around outside

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STAGE 3

• Syncytium invades into endometrium
• Invades maternal blood vessels causing blood to bath the blastocyst
• Blastocysts buries itself into endometrium

IMPLANTATION

STAGE 4

• Syncytium develops channels for maternal blood (called lacunae)
• Allows blastocyst to obtain oxygen and nutrients

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STAGE 5

• Synctyium enlarges and infiltrates deeper into endometrium
• Blastocyst is completely implanted into endometrium

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STAGE 6

• Blood vessels start to form which carry foetal blood

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CLINICAL CORRELATIONS

PLACENTA PRAEVIA

• Embryo implants near the cervix rather than high up the uterus
• Can grow over cervical OS so baby cannot be born vaginally
• Need to have a c section

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ECTOPIC

• Fertilised egg implants in an area outside of the uterus – usually the fallopian tubes
• Blastocyst then invades into tissue and finds blood vessel which can lead to internal bleeding
• SURGICAL EMERGENCY

MENSTRUAL CYCLE

1. FOLLICULAR PHASE
• Hypothalamus secretes GnRH causing pituitary to secrete FSH & LH
• FSH matures primary follicles
• Egg cells produce progesterone and oestrogen
• Above a certain level oestrogen causes positive feedback on pituitary to cause LH SURGE
• LH surge is what induces ovulation

MENSTRUAL CYCLE

2. OVULATION

• Occurs 36 hours after LH surge
• In regular cycle occurs at day 14
• Meiosis I is resumed in oocyte
• Oocyte is release from ovary and can survive for 24 hours unless fertilised

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3, LUTEAL PHASE

• Is progesterone dominant
• Follicle undergoes luteinisation to form corpus luteum which secretes oestrogen & progesterone
• Negative feedback lowers LH and FSH levels

MENSTRUAL CYCLE

2 things can then happen:

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FERTILISATION

• If fertilised there is release of hCG from foetus
• This maintains the corpus luteum to continue to secrete progesterone
• This occurs until placenta can take over

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LUTEOLYSIS

• If no fertilisation there is no hCG production
• Causes degeneration of corpus luteum so progesterone and oestrogen levels decrease
• Menstruation occurs due to falling progesterone levels

FUNCTIONS OF PLACENTA

1. TAKES OVER PROGESTERONE AND OESTROGEN PRODUCTION
• Takes over from corpus luteum at 8 weeks
• Means hormone production will continue even if ovaries are removed
• Small dip in progesterone as this happens
• Progesterone acts to keep myometrium quiet as it stretches (decrease pain)

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2. PRODUCES hCG & HPL

• hCG levels start to decrease after placenta takes over
• HPL levels continue to increase = promote breast tissue development and lactation

FUNCTIONS OF PLACENTA

3. TRANSPORT MOLECULES

• Ions and amino acids transported by active transport
• Iron bound to transferring in blood (usually insoluble)

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4. PASSIVE IMMUNITY FROM MOTHER

• Trophoblasts have Fc receptor that bind immunoglobulins
• Takes up antibodies to foetus

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Rhesus D Antibodies

• Can be transferred from mother to foetus
• Causes rhesus disease in baby = attack RBC causing anaemia

EMBRYOLOGY (L11-14)

BILAMINAR DISC

Embryoblast of the inner cell mass forms a bilaminar disc

• Made up of epiblast and hypoblast

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EPIBLAST/ECTODERM = future embryo

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HYPOBLAST/ENDODERM = creates no future structures and will die

GASTRULATION

Occurs at day 16 (formation of mesoderm

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Primitive streak appears on epiblast/endoderm and creates antero-posterior body axis

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Cells are pushed towards primitive streak and dip underneath

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Cells push between ectoderm and endoderm to create middle layer called mesoderm

• Mesoderm does not cover 2 areas (mouth and anus)

DEVELOPMENT OF NOTOCHORD

Henson’s node contains form of mesoderm which expands as primitive streak retreats

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Causes production of notochord down midline

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Notochord is a small area of dense mesoderm

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FUNCTION = sends signals to overlying ectoderm to differentiate into neural plate

NEURALATION

Is the folding process to create vertebrae

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Notochord releases growth factors causing it to fold in on itself to form neural tube

• Neural plate creases inwards and 2 ends eventually join
• Neural tube develops on top of notochord (acts as guideline)

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On either side of neural tube are the neural creast cells

• These are temporary cells that migrate around body and give rise to lots of cell types

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Neural tube later goes onto become the brain and spinal cord (CNS)

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WHAT EVERYTHING BECOMES

NEURAL TUBE = CNS (brain and spinal cord)

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ECTODERM = overlying skin

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ENDODERM = gut, lungs, liver, pancreas

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NEURAL CREST CELLS

1. Melanocytes = sit under dermis
2. Dorsal root ganglion = connect PNS and CNS
3. Facial mesenchyme = form packing tissue in face
4. Neuro-endocrine cells = specialised cells (e.g. adrenal glands)

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DEVELOPMENT OF BRAIN

Front part of neural tube develops into 3 vesicles

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This occurs around week 4, triggered by region specific induction

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1^st VESICLE = FOREBRAIN

1. Talencephalon = swells to form lateral 2 hemisphere of brain
2. Diencephalon = has 2 stalks growing at either side and become the future eyes

DEVELOPMENT OF BRAIN

2^nd VESICLE = MIDBRAIN (MESENCEPHALON)

• Forms small duct called aqueduct of Sylvius
• This allows fluid to drain from brain to spinal cord to prevent hydrocephalus

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3^rd VESICLE = HINDBRAIN

• Divides into cerebellum (metencephalon) and medulla oblongata (myelencephalon)

CLINICAL CORRELATIONS

Hydrocephalus = water on the brain

• Occurs due to a narrow or destroyed aqueduct of Sylvius and prevents fluid flowing out of the brain
• Causes cerebral hemispheres to swell up

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Microcephaly = small brain

• This is due to lack of forebrain induction

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Anencephaly

• More serious failure of induction where most of the brain is absent due to front end of neural tube failing

CLINICAL CORRELATIONS

Spina bifida is a neural tube defect with varying severity

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1. Occulta = bony projections don’t close and leaves a gap but this is covered by skin and not visible (least severe)

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• Meningocoel = arch doesn’t form properly meaning the meninges may herniate out forming a fluid filled blisters on surface which can cause infection

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• Myelocoel = bony canal remains open so neural tube lifts out
• This means area of the body doesn’t develop properly as there are no spinal nerves (most severe)

DEVELOPMENT OF UROGENITAL SYSTEM

Come from mesoderm

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Initially form 3 structures

1. Pronephros = degenerates by week 4
2. Mesonephros = develops excretory tubules which persist but rest degenerates by week 12
3. Metanephros = develop into kidneys

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In females = mesonephric duct degenerates and only duct persists to form uterus, vagina and fallopian tubes

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In males = mesonephric duct persists and forms spermatic cord

DEVELOPMENT OF HEART

Starts to develop at week 3-4

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Starts as a long tube with 3 chambers = atrium, ventricle, arterial trunk

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Partitions then occur to divide the ventricle and atrium into 2 chambers

• Issues here will lead to VSD/ASD/AVSD

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Division occurs in truncus arteriosus to form aorta and pulmonary artery

DEVELOPMENT OF GUT

Formed from endoderm

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Gut tube grows rapidly so embryo does not have space

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There is herniation of gut into umbilicus

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Midgut protrudes forming a loop

• SMA forms at the axis of this loop to supply midgut

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Midgut then makes quarter turn anticlockwise

• Distal part becomes caecum, proximal part coils around larger loop to become small bowel

DEVELOPMENT OF GUT

Body grows and becomes large enough for gut to return

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Original large loop becomes large colon

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Distal coiled segment becomes small colon

MUTATIONS AND TYPES OF INHERITANCE (L18-24)

MUTATIONS

Is a change in base sequence in a section of DNA

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Types of Mutation

• Silent = base change does not change amino acid
• Missense = change to a codon for another amino acid, if similar no effect but if dissimilar then function of protein is altered
• Nonsense = change from amino acid to STOP codon leading to premature truncation (harmful)
• Frame-shift = insertion or deletion of base pair which shifts everything else
• Splice-site = change that results in altered RNA sequence due to exon skipping

CAUSES OF MUTATIONS

EXTRACELLULAR

• UV light = disrupts structure and stops DNA replication
• Chemicals
• Ionising radiation

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INTRACELLULAR

• Depurination = deletion of base
• Reactive oxygen species
• Cytosines = spontaneous change from cytosine to thymine producing STOP codon (non-sense mutation)

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CHROMOSOMAL DISORDERS

STRUCTURE OF CHROMOSOME

• Centromere = joins sister chromatids, essential for chromosomal segregation
• Short arm (p) = anything ABOVE centromere
• Long arm (q) = anything BELOW centromere

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LINEAR INHERITENCE

• Occurs as chromosomes contain genes in linear order
• This means genes are inherited in blocks

TYPES OF CHROMOSOMAL DISORDERS

NUMERICAL

• Aneuploidy = monosomy, trisomy (3 copies of 1 chromosome)
• Polyploidy = triploidy (3 copies of every chromosome)

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STRUCTURAL

• Translocations = reciprocal or Robertsonian
• Deletions, duplications and inversions

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MOSAICISM

• Person has 2 or more genetically different sets of cells

ROBERTSONIAN TRANSLOCATION

2 chromosomes join together in an abnormal way

• E.g. 2 long arms of 2 separate chromosomes fuse to create one chromosome and the short arms are lost

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Occurs primarily between chromosome 21 and 14

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Results in genetic disorders such as Down’s and Patau syndrome

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Can be balanced (healthy but carrier) or unbalanced (will have disease)

RECIPROCAL TRANSLOCATION

Occurs during meiosis when there is exchange of chromosomal material

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Can occur in ANY chromosome

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Is balanced as there is no gain or loss of DNA

POSSIBLE CHROMOSOMAL DISORDERS

Down Syndrome (Trisomy 21)

• Facial appearance, mental handicap, congenital heart malformations, floppy baby, tongue protrudes

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Patau Syndrome (Trisomy 13)

• Midline structures affected, incomplete brain lobation, cleft lip, gut herniation, congenital heart disease

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Edwards Syndrome (Trisomy 17)

• Heart and kidney malformation, clenched hands, overlapping fingers, altered contraction of muscles

Klinefelter syndrome (47 XXY): 1 in 1000 males

• Associated with infertility (testes produce no sperm)
• Poorly developed secondary sexual characteristics
• Often tall

Turner Syndrome (45, X): 1 in 5000 females

• Spontaneous loss in pregnancy, short stature
• Ovaries involute before birth
• Congenital heart disease and problems with lymphatic system

POSSIBLE CHROMOSOMAL DISORDERS

AUTOSOMAL DOMINANT DISORDERS

Condition where if person has 1 copy of allele/gene they will have disease (Gg)

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Pedigree

• Wide spread of people affected
• BOTH male and female
• Disorder is in every generation
• All forms of transmission seen (including male to male)

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If 1 parent has condition the likelihood of passing on is 50%

AUTOSOMAL DOMINANT DISORDERS

VARIATION IN EXPRESSION

• Family members have different signs/severities of same disease

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INCOMPLETE PENETRANCE

• Symptoms are not always present in individuals who have mutation
• Complete penetrance = everyone with mutation has 1 symptoms

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ANTICIPATION

• In successive generation the age of onset gets younger and severity increases

AUTOSOMAL RECESSIVE DISORDERS

Condition that only manifests when mutation is in BOTH alleles (e.g. gg)

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Pedigree

• Seems to have no pattern
• Siblings affected (child has disease but parents do not)
• Incidence in both males and females
• Could be evidence of consanguinity (related by blood)

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Means both parents need to be carriers (have 1 copy) for child to be effected

• If both parents are carriers the risk to offspring is 25%

EXAMPLES OF RECESSIVE DISORDERS

SPINAL MUSCULAR ATROPHY

• Weakness and wasting of proximal muscles
• Severe form causes death by 2 years

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CYSTIC FIBROSIS

• Chronic lung disease effecting exocrine glands
• Caused by mutation in CFTR gene

X LINKED CONDITIONS

Condition found on X chromosome

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Means for female to be affected it must be in BOTH X chromosomes but for male to be effected in is only in 1

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Pedigree

• Occurs across more than 1 generation
• Usually only males affected
• No male to male transmission (tends to be fatal)

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EXAMPLES = Duchenne and Becker Muscular Dystrophy

MITOCHONDRIAL INHERITENCE

Mitochondria has own DNA

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Are exclusively MATERNALLY inherited as sperm mitochondria are expelled from egg

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Characteristics

• Only from effected mother
• Multisystem as in ALL cells of body

MULTIFACTORIAL INHERITENCE

Condition follows no inheritance process

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Effected by both many genes (polygenic) and environmental factors

• E.g. coronary artery disease, diabetes, HTN

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Generally only 1 organ system is affected

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Probability of recurrence is determined by population studies

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