Genetic Diseases — Cystic Fibrosis, PKU, Huntington's Disease, Type 1 Diabetes

Activity 1 — Gene-Protein-Phenotype Identification

1. Huntington's disease. Gene: HTT (chromosome 4) — expanded CAG trinucleotide repeats. Protein: mutant huntingtin with an abnormally long polyglutamine (polyQ) tract — this protein misfolds and aggregates into insoluble clumps preferentially in striatal and cortical neurons. Why these symptoms: the polyQ huntingtin aggregates disrupt proteasome function and mitochondrial activity in striatal neurons specifically → progressive neuronal death in the basal ganglia → chorea (involuntary movements), cognitive decline. The affected parent is consistent with autosomal dominant inheritance — 50% chance of inheriting the expanded allele.

2. PKU. Gene: PAH (chromosome 12). Both parents are healthy carriers — each has one mutated PAH allele and one normal allele (Pp). The child is pp (two mutated alleles, autosomal recessive). Carriers produce enough functional phenylalanine hydroxylase from their one normal allele to metabolise phenylalanine normally → no symptoms. The child has no functional PAH → phenylalanine accumulates → toxic to neurons. Immediate dietary intervention is critical because brain damage from phenylalanine accumulation begins in infancy and is irreversible — the earlier the low-phenylalanine diet begins, the less neurological damage occurs.

3. Type 1 diabetes. Anti-islet cell antibodies indicate the immune system has been producing antibodies against the beta cells of the islets of Langerhans — confirming the autoimmune mechanism. Undetectable C-peptide confirms that insulin production by beta cells has ceased (C-peptide is released alongside insulin; its absence confirms no insulin being produced). Blood glucose is elevated because without insulin, cells cannot take up glucose despite the hyperglycaemia — the pancreas is structurally present but its beta cells have been destroyed by the autoimmune attack. Gene → protein → phenotype: HLA genetic variants → impaired immune self-tolerance → T cells attack beta cells → beta cells destroyed → no insulin produced → hyperglycaemia and ketoacidosis.

4. Cystic fibrosis. The elevated sweat chloride result is explained by CFTR function: normally, CFTR in sweat duct epithelium reabsorbs Cl⁻ from sweat before it reaches the skin surface — so normal sweat is low in Cl⁻. In CF, without functional CFTR, Cl⁻ cannot be reabsorbed from the sweat duct → Cl⁻ concentration in sweat remains high → elevated sweat chloride test result. This is the basis of the diagnostic sweat chloride test (>60 mmol/L is diagnostic). Gene → protein → phenotype: CFTR F508del mutation → misfolded protein degraded → no Cl⁻ channel → Cl⁻ not secreted into airways (or reabsorbed from sweat duct) → thick mucus / high sweat Cl⁻ → chronic infection, lung damage.

5. CF vs Huntington's comparison: CF: inheritance = autosomal recessive; mechanism = loss of function (CFTR channel absent/non-functional); age of onset = present from birth (symptoms manifest in infancy). Huntington's: inheritance = autosomal dominant; mechanism = gain of function (toxic polyQ huntingtin produced); age of onset = typically 30–50 years. Why mechanism explains inheritance: Huntington's is dominant because the mutant protein is actively toxic — even one normal HTT allele producing normal huntingtin does not neutralise the toxic effects of the mutant protein from the other allele. CF is recessive because it is a loss-of-function — one functional CFTR allele produces enough chloride channel protein to maintain adequate Cl⁻ secretion. Having 50% of normal CFTR is sufficient to prevent disease (this is why carriers are unaffected).

Activity 2 — Unfamiliar Disease (FH)

(a) Gene-protein-phenotype: Gene = LDLR (LDL receptor gene) → Protein = non-functional or absent LDL receptor on liver cell membranes → LDL particles cannot be taken up by liver cells → LDL accumulates in blood → deposits in artery walls → atherosclerosis → premature cardiovascular disease.

(b) Dominant or recessive? FH is autosomal dominant. Evidence: the heterozygous form (one mutant allele, one normal) causes moderately elevated LDL and cardiovascular disease — the single normal LDLR allele does not produce enough receptor protein to clear LDL adequately when the other allele is non-functional. This is a gene dosage effect — 50% of normal receptor expression is insufficient to maintain normal LDL clearance. Compare with CF: one normal CFTR allele is sufficient to maintain adequate Cl⁻ secretion (carriers are healthy), making CF recessive. In FH, one normal allele is insufficient, making FH dominant.

(c) Loss or gain of function? Loss-of-function mutation — the LDL receptor is absent or non-functional; it fails to perform its normal role (LDL uptake into liver cells). The mutant protein does not do anything new or toxic; it simply fails to do what it normally would.

(d) Why genetic rather than environmental: FH is a genetic disease because it is caused by a specific mutation in the LDLR gene that is present from birth and causes elevated LDL regardless of diet. A person with FH on a very low-fat diet will still have significantly elevated LDL compared to a person without FH on the same diet. Diet influences LDL in the general population through the amount of LDL produced, but FH specifically impairs the clearance mechanism (receptor-mediated uptake) — this is a molecular defect in a specific protein, not a response to dietary excess. The disease is classified as genetic because the primary causal mechanism is the gene mutation, not dietary behaviour.

Multiple Choice

1. B — CFTR mutation → misfolded protein → no Cl⁻ channel → Cl⁻ not secreted → water not secreted → dehydrated/thick mucus. Option A describes an autoimmune mechanism (which is Type 1 diabetes, not CF). Option C incorrectly attributes overproduction to goblet cells. Option D incorrectly describes the CFTR protein as an insoluble blocker.

2. C — Huntington's is dominant because it is gain-of-function — the toxic protein causes harm regardless of the normal allele. CF is recessive because it is loss-of-function — one functional allele produces enough CFTR for normal physiology. Option A is wrong — it is not about the number of genes. Option B is wrong — severity does not determine inheritance pattern. Option D is wrong — both are autosomal; CF is not X-linked.

3. D — ~50% concordance in identical twins (who share 100% DNA) shows that genetic predisposition is necessary but not sufficient — environmental factors must also trigger the autoimmune destruction. Option A is wrong — the higher-than-population concordance shows significant genetic contribution. Option B misinterprets the data as standard Mendelian. Option C is incorrect — Type 1 diabetes is not contagious.

4. A — PKU is autosomal recessive. Both parents are carriers (Pp). Two carriers have a 25% chance of producing a pp child. One normal PAH allele produces enough phenylalanine hydroxylase to metabolise phenylalanine normally in carriers. Option B is possible in principle but statistically very unlikely given the carrier frequency — the most parsimonious explanation is carrier parents. Option C is wrong. Option D is wrong — PKU is recessive, not dominant.

5. C — With 48 CAG repeats (well above the 40 threshold), this individual will almost certainly develop Huntington's disease if they live long enough. The disease has very high (approaching 100%) penetrance at this repeat length. At 35, they are likely pre-symptomatic — the mutant huntingtin has been accumulating since birth and neurons in the striatum are already dying, but insufficient neuronal loss has yet occurred to produce detectable clinical symptoms. Option A is wrong — 48 repeats gives near-complete penetrance. Option B is wrong — 35 is well within the typical range for onset. Option D is partially correct (accumulation has begun) but incorrectly states they are already 'affected' in a clinical sense — symptoms have not appeared.

Short Answer Model Answers

Q6 (4 marks): Gene: the CFTR gene on chromosome 7 carries a mutation — most commonly the F508del deletion, which removes the codon for phenylalanine at position 508 of the protein [1 mark]. Protein: the mutant CFTR protein misfolds and is recognised by cellular quality control mechanisms and degraded in the endoplasmic reticulum before it can be inserted into the cell membrane. The result is that the epithelial cells lining the airways have no functional Cl⁻ ion channel in their apical membrane [1 mark]. Cellular consequence: without CFTR, Cl⁻ cannot be secreted from the epithelial cell into the airway lumen. Because Cl⁻ does not accumulate in the lumen, water does not follow by osmosis — the airway surface liquid is depleted of water and the mucus layer becomes thick, viscous, and dehydrated [1 mark]. Lung consequences: dehydrated mucus cannot be cleared effectively by ciliary action (mucociliary clearance fails) — it accumulates in the airways, obstructing airflow and creating an ideal environment for bacterial colonisation (particularly Pseudomonas aeruginosa and Staphylococcus aureus). Recurrent bacterial infections trigger chronic inflammation → progressive lung damage → respiratory failure over years to decades [1 mark — 4 marks total].

Q7 (5 marks): (a) PKU protein mechanism: mutations in the PAH gene produce a non-functional phenylalanine hydroxylase enzyme that cannot catalyse the conversion of phenylalanine to tyrosine. This is a loss-of-function mutation — the enzyme is simply absent or inactive [1 mark]. Huntington's protein mechanism: expansion of CAG trinucleotide repeats in the HTT gene produces a mutant huntingtin protein with an abnormally long polyglutamine (polyQ) tract. This is a gain-of-function mutation — the mutant protein folds abnormally and forms toxic aggregates that accumulate in neurons, actively damaging them [1 mark]. (b) Inheritance pattern explanation: PKU is autosomal recessive because one normal PAH allele produces sufficient phenylalanine hydroxylase to metabolise phenylalanine normally — 50% of normal enzyme activity is adequate. The loss of one allele does not cause disease. Huntington's is autosomal dominant because having one normal HTT allele does not protect against the toxic effects of the mutant huntingtin protein produced by the other allele — the toxic protein causes harm independently of what the normal allele produces [2 marks]. (c) Dietary management: PKU is managed with diet because the damage depends on the accumulation of phenylalanine — a dietary amino acid. By restricting phenylalanine intake, the substrate that accumulates is removed and the enzyme deficiency becomes clinically irrelevant. Huntington's cannot be managed with diet because the toxic huntingtin protein is produced endogenously from the mutant allele regardless of diet — there is no dietary substrate to restrict. Current therapies aim to reduce mutant HTT expression (e.g. antisense oligonucleotides in clinical trials) but none are yet clinically approved [1 mark — 5 marks total].

Q8 (5 marks): Evidence supporting genetic classification: Type 1 diabetes has clear genetic risk factors — specific HLA alleles (particularly HLA-DR3 and HLA-DR4) are present in approximately 90% of Type 1 diabetics. First-degree relatives of affected individuals have a 5–10× increased lifetime risk compared to the general population (~0.4%). Multiple genome-wide association studies have identified over 50 genetic loci contributing to risk. The autoimmune destruction of beta cells has a genetic basis in the immune system's failure to maintain self-tolerance [1 mark]. Evidence complicating the classification: identical twin concordance is only approximately 50%. Since identical twins share 100% of their DNA, if Type 1 diabetes were purely genetic, concordance should approach 100%. The 50% figure demonstrates that genetic predisposition alone is insufficient — an environmental trigger is also required [2 marks]. Role of environmental factors: proposed triggers include enteroviral infections (e.g. Coxsackievirus B), early dietary exposures (timing of gluten or cow's milk introduction), gut microbiome composition, and vitamin D status. These environmental factors are thought to trigger or accelerate the autoimmune response in genetically susceptible individuals [1 mark]. Conclusion: the classification as a 'genetic disease' is appropriate in the sense that genetic predisposition is necessary for the disease to develop. However, it is more accurate to describe Type 1 diabetes as a disease of genetic predisposition requiring environmental triggering — a multifactorial disease in which genetic susceptibility (particularly HLA variants) interacts with environmental exposures to produce the autoimmune destruction of beta cells. The label 'genetic disease' alone risks overstating the genetic determinism and understating the preventive potential of identifying and modifying environmental triggers [1 mark — 5 marks total].