Which disorder is caused by substitution of Glutamic acid (Glu)

BiologyGenetics

Which disorder is caused by substitution of Glutamic acid (Glu)
by Valine (Val) at the 6th position of the beta globin chain?

Options

Haemophilia

Thalassemia

Sickle-cell anaemia

Phenylketonuria

Correct Answer

Option 3 : Sickle-cell anaemia

Solution

Point mutation in β-globin gene (HBB, chromosome 11):

6th codon: GAG (Glutamic acid, Glu) → GUG (Valine, Val)

This is the classic mutation causing sickle cell anaemia.

Glu (charged/hydrophilic) → Val (hydrophobic) at position 6 creates a sticky patch on HbS → polymerisation → RBC sickling → anaemia + vascular blockage.

Haemophilia = clotting factor deficiency (X-linked) — NOT Hb mutation.

Thalassaemia = reduced Hb production — NOT structural change at position 6.

PKU = phenylalanine hydroxylase deficiency — NOT Hb related.

Glu⁶ → Val⁶ in β-globin = Sickle cell anaemia
HbA → HbS — autosomal recessive

Theory: Genetics

1. Sickle Cell Anaemia — A Classic Genetic Disorder

Sickle cell anaemia is one of the most important and well-studied genetic disorders, serving as a model for understanding molecular disease mechanisms, population genetics, and natural selection. It is caused by a point mutation (single base change) in the HBB gene (haemoglobin beta-chain gene) on chromosome 11. The mutation: at the 6th codon of the beta-globin gene, a single nucleotide change from A→T in the mRNA codon (GAG→GUG) → glutamic acid (Glu, acidic, hydrophilic) is replaced by valine (Val, non-polar, hydrophobic). This single amino acid change dramatically alters haemoglobin's behaviour and causes the disease.

2. Molecular Mechanism — Why One Change is So Devastating

The substitution of glutamic acid (Glu, charged) by valine (Val, hydrophobic) at position 6 of the β-chain creates a new hydrophobic surface patch on the haemoglobin molecule. When HbS (sickle haemoglobin) releases oxygen (deoxygenation): the hydrophobic patch on one HbS molecule binds to a complementary hydrophobic pocket on an adjacent deoxygenated HbS molecule → progressive polymerisation → long fibrous aggregates of HbS molecules form within the RBC → the RBC distorts into a sickle (crescent) shape. Sickle-shaped RBCs: fragile → haemolysis (premature destruction → anaemia). Stiffer than normal → block small capillaries → vaso-occlusive crises → pain, organ damage. Shorter life span (~20 days vs normal 120 days) → chronic anaemia. Sickle crises are triggered by low O₂ (altitude, infection), dehydration, cold, physical stress.

3. Inheritance Pattern — Autosomal Recessive

Sickle cell anaemia is an autosomal recessive disorder. The HBB gene is on chromosome 11 (autosome, not sex chromosome). Genotypes: HbA/HbA (normal homozygous): makes only normal haemoglobin. Healthy. HbA/HbS (carrier = sickle cell trait): makes both HbA and HbS. Usually asymptomatic (mild symptoms at extreme conditions). HbS/HbS (sickle cell anaemia): makes only HbS. Full disease. If both parents are HbA/HbS carriers: probability of HbS/HbS offspring = 25% (1/4). This 1:2:1 ratio (HbAA:HbAS:HbSS) is the classic Mendelian ratio for autosomal recessive inheritance. Co-dominance aspect: in carriers, BOTH HbA and HbS are expressed (both types of haemoglobin present) → this is actually an example of co-dominance at the protein level, though the disease is inherited as recessive.

4. Malaria and Sickle Cell — Natural Selection in Action

The HbS allele is maintained at high frequency (10-40%) in malaria-endemic regions of Africa, Mediterranean, Middle East, and India — a phenomenon known as balanced polymorphism or heterozygote advantage. Explanation: HbS/HbS (sickle cell disease): severely ill, reduced fitness. HbA/HbA (normal): susceptible to malaria → Plasmodium falciparum infects and grows in normal RBCs. Severe malaria → death. HbA/HbS (carrier): infected RBCs sickle when malaria parasite inside → parasite-infected cells are removed by spleen before parasite can complete cycle → heterozygote is PROTECTED against severe malaria. Carriers have higher survival in malaria-endemic areas → natural selection maintains HbS allele. In non-malaria regions (e.g., North America), selection no longer favours HbS → frequency declining in African-American population over generations. This is a classic example of evolution by natural selection.

5. Diagnosis and Treatment

Diagnosis: Newborn screening: solubility test or haemoglobin electrophoresis. HbS migrates differently from HbA in electrophoresis (different charge due to Val instead of Glu). Prenatal diagnosis: amniocentesis or chorionic villus sampling → fetal DNA → PCR + restriction enzyme analysis (the mutation creates/destroys a restriction site). Genetic testing: direct DNA sequencing. Sickle cell preparation test: blood sample mixed with reducing agent (sodium metabisulfite) → deoxygenation → sickle cells visible under microscope. Treatment: Hydroxyurea: increases fetal haemoglobin (HbF) production → dilutes HbS → reduces sickling → FDA approved 1998. Blood transfusions: correct anaemia, dilute HbS. Bone marrow/stem cell transplant: only cure, limited by donor availability and risks. Gene therapy: CRISPR-based approaches to reactivate fetal haemoglobin gene → promising results in clinical trials (2023-24).

6. Haemoglobin Structure and Function

Normal haemoglobin (HbA): tetramer of 4 polypeptide chains (2α + 2β) each carrying one haem group (iron-porphyrin). Quaternary structure: 4 subunits interact cooperatively. O₂ binding: sigmoid curve (cooperative binding — one O₂ bound increases affinity for next). T state (tense, deoxyHb): low O₂ affinity. R state (relaxed, oxyHb): high O₂ affinity. Bohr effect: lower pH or higher CO₂ → reduces O₂ affinity → O₂ released in tissues (where CO₂ and H⁺ are high). 2,3-DPG: binds to deoxyHb → reduces O₂ affinity → facilitates O₂ delivery to tissues. Foetal haemoglobin (HbF): has γ-chains instead of β → higher O₂ affinity than HbA → ensures O₂ transfer from mother to foetus. Haemoglobin variants: HbA (normal), HbA2 (small amount, δ-chains), HbF (foetal), HbS (sickle), HbC (another β-chain variant).

7. Other Haemoglobin Disorders

Thalassaemia: quantitative defect — reduced production of normal globin chains (not a structural change). α-thalassaemia: reduced α-chain production. β-thalassaemia: reduced β-chain production. Results in anaemia (fewer functional Hb tetramers) and accumulation of excess unpaired chains (which damage RBCs). More common in Mediterranean, Middle East, South/Southeast Asia. Haemoglobin C disease: another β-chain mutation (Glu⁶→Lys in HbC). Milder than sickle cell. HbSC disease: one HbS + one HbC allele → intermediate severity. Haemophilia: NOT a haemoglobin disorder — it is a blood clotting factor deficiency. Haemophilia A: Factor VIII deficiency (X-linked recessive). Haemophilia B: Factor IX deficiency (X-linked recessive). Phenylketonuria (PKU): phenylalanine hydroxylase deficiency (autosomal recessive) — NOT a haemoglobin disorder.

8. Genetic Disorders — Classification

Mendelian genetic disorders: Autosomal dominant: Huntington's disease, Marfan syndrome, achondroplasia (dwarfism), polydactyly (extra fingers). Autosomal recessive: sickle cell anaemia, cystic fibrosis, phenylketonuria, alkaptonuria, albinism, thalassaemia. X-linked recessive: haemophilia A and B, Duchenne muscular dystrophy, colour blindness, G6PD deficiency. X-linked dominant: hypophosphataemic rickets. Chromosomal disorders: Trisomy: Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13). Sex chromosome: Turner syndrome (45,X = XO), Klinefelter (47,XXY), Triple-X (47,XXX), XYY syndrome. Multifactorial: influenced by multiple genes + environment (cardiovascular disease, diabetes, asthma). Imprinting disorders: Prader-Willi syndrome (paternal 15q deletion), Angelman syndrome (maternal 15q deletion).

Frequently Asked Questions

1. What exactly is the mutation causing sickle cell anaemia? ⌄

Single nucleotide substitution in HBB gene (β-globin gene, chromosome 11, position 6): DNA: GAG → GTG (at DNA level, sense strand). mRNA: GAG → GUG (codon 6 of β-globin mRNA). Protein: Glutamic acid (Glu, codon 6) → Valine (Val). Glutamic acid has a negatively charged side chain (−CH₂−COOH, pKa ~4). Valine has a non-polar, hydrophobic side chain (−CH(CH₃)₂). This charge change at position 6 of the 146-amino-acid β-chain is the ENTIRE cause of sickle cell anaemia — a profound example of how a single base change can cause a devastating disease.

2. Why does sickle cell anaemia cause both anaemia AND vessel blockage? ⌄

Two distinct mechanisms: (1) Anaemia: sickle-shaped RBCs are fragile → haemolysis (rupture) → RBCs live only ~20 days (vs normal 120 days) → body cannot compensate → chronic anaemia → fatigue, pallor, shortness of breath. (2) Vascular occlusion (sickle cell crisis): sickle cells are rigid and sticky → block small capillaries (vaso-occlusion) → tissue beyond blockage is deprived of O₂ → ischemic pain crisis. Crises can affect: bones (acute chest syndrome, bone pain), brain (stroke), spleen (autosplenectomy — repeated infarctions cause spleen to atrophy in childhood), kidney, penis (priapism). Fever/infection/dehydration/altitude/cold trigger crises by causing deoxygenation.

3. What is the difference between sickle cell trait and sickle cell disease? ⌄

Sickle cell TRAIT (HbAS, carrier): one HbA gene + one HbS gene. Makes both HbA and HbS. Usually ASYMPTOMATIC in normal conditions — HbA dilutes HbS enough to prevent most sickling. May have mild sickling at extreme low O₂ (high altitude, intense exercise). NOT a disease — a carrier state. Protects against malaria (heterozygote advantage). Sickle cell DISEASE (HbSS): two HbS genes. Makes ONLY HbS. Full clinical disease: chronic haemolytic anaemia, recurrent pain crises, organ damage, shortened lifespan. Requires medical management. Distinction: trait = carrier = asymptomatic usually; disease = homozygous = symptomatic.

4. How is sickle cell anaemia diagnosed? ⌄

(1) Sickling test (Itano solubility test): blood + sodium metabisulphite (reducing agent) → deoxygenates HbS → HbS polymerises → turbid solution (vs clear for HbA). Simple screening test. (2) Haemoglobin electrophoresis: separates Hb variants by size/charge. HbS moves differently from HbA (less negative charge due to Val replacing Glu → migrates more slowly toward anode). Distinguishes HbAA, HbAS, HbSS, HbCC etc. (3) HPLC (High Performance Liquid Chromatography): quantifies different Hb fractions. Gold standard for diagnosis. (4) DNA-based testing: PCR + restriction digest (DdeI or MstII — the mutation destroys the restriction site). Or direct sequencing. Used for prenatal diagnosis.

5. Why is sickle cell anaemia more common in malaria-endemic regions? ⌄

Balanced polymorphism / heterozygote advantage: In malaria-endemic regions: HbSS → dies of sickle cell anaemia (−). HbAA → susceptible to Plasmodium falciparum malaria → may die (−). HbAS (carrier) → partially protected against severe malaria PLUS healthy → survives and reproduces (+). Selection pressure: HbAS carriers have higher survival and reproductive fitness in malaria regions → they pass HbS to more offspring → allele frequency of HbS stays high (10-40% in some African populations). In non-malaria regions (e.g., North America): No malaria protection benefit for HbAS. Only HbSS disadvantage remains → natural selection will slowly reduce HbS frequency over generations. This is why sickle cell anaemia is most prevalent in Sub-Saharan Africa, Mediterranean, Middle East, and parts of India — all historically malaria-endemic regions.

6. Compare sickle cell anaemia with thalassaemia. ⌄

Sickle cell anaemia: Structural haemoglobin disorder — abnormal β-chain (Glu⁶→Val). HbS produced in normal amounts but sickles when deoxygenated. Autosomal recessive. Mainly affects African, Middle Eastern, Mediterranean, Indian populations. Thalassaemia: Quantitative haemoglobin disorder — reduced production of normal α or β chains (gene deletions/mutations that affect expression level). α-thalassaemia: reduced α-chain → excess β-chains → HbH (β₄) in adults, Hb Barts (γ₄) in infants. β-thalassaemia: reduced β-chain → excess α-chains → aggregate, cause RBC damage. Autosomal recessive. Mainly Mediterranean, Middle Eastern, South/Southeast Asian populations. Both: treatable with hydroxyurea, transfusions; curable with stem cell transplant. Key distinction: sickle cell = structural (wrong amino acid); thalassaemia = quantitative (not enough normal chain).

7. What are the types of point mutations? ⌄

Point mutation = change in a single base pair. Types by effect on protein: Silent (synonymous): codon changed → but same amino acid (due to degeneracy of genetic code). No effect on protein. Missense: codon changed → different amino acid. May be: Conservative (similar properties — Glu→Asp, both acidic → may not affect function much) or Non-conservative (very different properties — Glu→Val as in sickle cell → drastically changes function). Nonsense: codon changed → stop codon (UAA, UAG, UGA). Premature termination → truncated, usually non-functional protein. Readthrough mutation: stop codon → amino acid codon → elongated protein. Frameshift mutations (not point mutations, but related): insertion or deletion of bases → shifts reading frame → completely different downstream amino acids → usually severely disrupted protein.

8. What is the prognosis and treatment for sickle cell patients? ⌄

With modern medical care, life expectancy has dramatically improved: Without treatment (developing world): median survival ~40-50 years in patients with access to basic care. With comprehensive care (developed world): many patients live into 50s-60s. Treatment: Hydroxyurea (HU): increases production of foetal haemoglobin (HbF, which doesn't sickle). HbF dilutes HbS → reduces sickling, fewer crises, lower hospitalisations. FDA-approved 1998. Pain management: NSAIDs, opioids during crises. Infections prevented by: penicillin prophylaxis (as spleen is non-functional → vulnerable to encapsulated bacteria), pneumococcal/meningococcal/Hib vaccines. Blood transfusions: for severe anaemia, stroke prevention. Curative: bone marrow stem cell transplant (BMT) — ~90% cure rate if matched donor. Gene therapy (2023-24): clinical trials showing promising results — inserting functional HBB gene or using CRISPR to reactivate HbF. Potential cure without matched donor needed.

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