explain the relationship between genes, proteins and phenotype with respect to the: TYR gene, tyrosinase and albinism, HBB gene, haemoglobin and sickle cell anaemia, F8 gene, factor VIII and haemophilia, HTT gene, huntingtin and Huntington’s disease

Objective

Explain the relationship between genes, the proteins they encode and the resulting phenotype, using the following examples:

• TYR gene – tyrosinase – albinism
• HBB gene – haemoglobin – sickle‑cell anaemia
• F8 gene – factor VIII – haemophilia A
• HTT gene – huntingtin – Huntington’s disease

General Framework

The flow of genetic information can be summarised as:

1. Gene (DNA) – a specific sequence of nucleotides located on a chromosome.
2. Transcription – the gene is copied into messenger RNA (mRNA) in the nucleus.
3. Translation – ribosomes read the mRNA to synthesise a polypeptide chain (protein).
4. Protein function – the protein’s structure determines its biochemical activity.
5. Phenotype – the observable trait or disease state that results from the protein’s activity (or lack thereof).

Case Studies

1. TYR Gene – Tyrosinase – Albinism

Gene: TYR located on chromosome 11q14.3.

Protein product: Tyrosinase, a copper‑containing enzyme that catalyses the first two steps in melanin synthesis:

• Tyrosine → DOPA
• DOPA → DOPAquinone

Melanin pigments give colour to skin, hair and eyes.

Phenotypic effect of mutations:

• Loss‑of‑function mutations (missense, nonsense, frameshift) reduce or abolish enzyme activity.
• Result: little or no melanin is produced → oculocutaneous albinism (OCA1).
• Clinical features: pale skin, white hair, light‑coloured irises, visual problems.

2. HBB Gene – Haemoglobin – Sickle‑Cell Anaemia

Gene: HBB on chromosome 11p15.5, encodes the β‑globin chain of adult haemoglobin.

Normal haemoglobin structure: \$\alpha2\beta2\$ (two α‑chains and two β‑chains).

Common mutation: A single‑base substitution (A→T) in the sixth codon of HBB changes the codon from GAG (glutamic acid) to GTG (valine). This is written as:

\$\text{β}^{\text{S}}: \text{Glu}^{6} \rightarrow \text{Val}^{6}\$

Effect on protein:

• Valine is hydrophobic; its presence creates a sticky patch on the β‑chain surface.
• Under low oxygen tension, haemoglobin S (HbS) polymerises, distorting red blood cells into a sickle shape.

Phenotypic consequences:

• Reduced oxygen‑carrying capacity.
• Chronic haemolytic anaemia, vaso‑occlusive crises, organ damage.

3. F8 Gene – Factor VIII – Haemophilia A

Gene: F8 on the X chromosome (Xq28).

Protein product: Coagulation factor VIII, a large glycoprotein that acts as a co‑factor for factor IXa in the intrinsic pathway of blood clotting.

Normal cascade (simplified):

1. Factor X is activated to Xa by the intrinsic tenase complex (VIIIa·IXa).
2. Xa converts prothrombin to thrombin, leading to fibrin clot formation.

Mutations and phenotype:

• Large deletions, nonsense mutations, or splice‑site errors produce a non‑functional or absent factor VIII.
• Result: impaired intrinsic pathway → prolonged bleeding time.
• Clinical presentation: spontaneous joint haemorrhages, prolonged clotting after injury, haemarthrosis.

4. HTT Gene – Huntingtin – Huntington’s Disease

Gene: HTT on chromosome 4p16.3.

Protein product: Huntingtin, a large cytoplasmic protein of unknown precise function, involved in vesicular transport and transcription regulation.

Mutation type: Expansion of a CAG trinucleotide repeat in exon 1, encoding a polyglutamine (poly‑Q) tract.

Normal alleles: 10–35 repeats.

Pathogenic alleles: ≥36 repeats (often >40).

Pathogenic mechanism:

• Extended poly‑Q tract causes misfolding and aggregation of huntingtin.
• Aggregates interfere with neuronal transcription, mitochondrial function and axonal transport.
• Selective degeneration of medium spiny neurons in the striatum.

Phenotypic features:

• Progressive motor dysfunction (chorea, dystonia).
• Cognitive decline and psychiatric disturbances.
• Typically manifests in mid‑adulthood, with earlier onset for larger repeat numbers.

Summary Table

Key Take‑aways

• Genes encode proteins; the structure and activity of those proteins determine cellular function.
• Mutations can alter protein amount (e.g., null alleles) or protein structure (e.g., missense, repeat expansions).
• The phenotypic outcome depends on the role of the protein in physiology – loss of pigment, altered oxygen transport, impaired clotting, or neurotoxicity.
• Understanding the gene‑protein‑phenotype link is essential for diagnosis, genetic counselling and development of targeted therapies.