Genetics II Gene Disorders

Overview of Single-Gene Disorders

• Definition: Disorders caused by mutations in a single gene. These mutations do not alter the chromosomal number of $46$ nor result in structural deformities visible on a karyotype.
• Method of Study: Specialized pedigrees are the primary tool for determining single-gene disorders, whereas karyotypes are used for abnormalities in chromosomal number and structure.
• Transcription Patterns:
  • Mendelian Inheritance: Includes Autosomal Dominant ($AD$), Autosomal Recessive ($AR$), Sex-Linked Dominant, and Sex-Linked Recessive.
  • Non-Mendelian Inheritance: Includes Trinucleotide Repeat Mutation ($TRM$), Mutations in Mitochondrial Genes, Genomic Imprinting, and Gonadal Mosaicism.

Mendelian Inheritance: Autosomal Dominant ($AD$)

• Main Characteristics:
  • No Skip Generation: The trait appears in every generation. Only one affected allele from a parent is required for the offspring to manifest the disorder.
  • No Sexual Preference: Random distribution between males and females; the trait is transmitted via autosomes.
  • Offspring Probabilities: When one affected parent marries a normal person, each child has a $50\%$ chance of developing the disease.
• Incomplete Penetrance: The ability of individuals carrying the abnormal gene to NOT express the trait phenotypically. They appear normal despite having the gene.
  • Probability of Expression: $50\%$ penetrance means a person has a $50\%$ chance of manifesting symptoms if they carry the gene. $80\%$ penetrance implies a $20\%$ chance that the case will not manifest despite carrying the abnormal gene.
• Variable Expressivity: Differences in the manner and severity in which the trait is expressed among different individuals carrying the gene.
  • Neurofibromatosis Example: One patient may have large multiple tumors on the skull and face (cranial nerve involvement), while another may have thousands of small neurofibromas scattered across the skin.
• New Mutations: If both parents are normal but an offspring develops an $AD$ disease, it indicates a new mutation. In established $AD$ lineages, at least one parent must carry the gene.

Mendelian Inheritance: Autosomal Recessive ($AR$)

• Main Characteristics:
  • Presence of Skip Generation: There are generations not phenotypically affected by the disease.
  • No Sexual Predilection: Transmission is autosomal.
  • Offspring Probabilities: If both parents are carriers, there is a $1:4$ ($25\%$‐) chance of an offspring being affected. If only one parent is a carrier, none of the children will manifest the disease.
  • Consanguinity: Often associated with marriage between kin (e.g., royalty), as rare recessive genes are more likely to meet within the same lineage.
• Clinical Features:
  • Complete Penetrance: Usually $100\%$‐.
  • Onset: Frequently early in life.
  • Expression: More uniform than $AD$ traits.
  • Carriers: Individuals with one abnormal gene dose do not manifest the disease; the abnormal gene must be present in both alleles (double dose) for manifestation.
• Sickle Cell Example: If both parents carry the sickle cell trait on autosome $11$, half the offspring are carriers, and one quarter ($25\%$‐) manifest the disease.

Mendelian Inheritance: Sex-Linked Dominant and Recessive

• Sex-Linked Dominant:
  • General: Rare; carried on the $X$ chromosome. The $Y$ chromosome is significantly inactive and only determines male sex.
  • No Skip Generation: All generations manifest the disease.
  • Sex Predilection:
    • Affected Male: Transmits to ALL daughters and NONE of the sons (sons receive only the $Y$ chromosome).
    • Affected Female: Transmits to $50\%$ of sons and $50\%$ of daughters.
  • Example: Vitamin D-Resistant Rickets (X-Linked Hypophosphatemic Rickets).
• Sex-Linked Recessive:
  • General: Almost all sex-linked conditions are recessive. Females are usually carriers.
  • Presence of Skip Generation: Traits go "underground" in carrier females.
  • Sex Predilection:
    • Affected Male: Does not transmit to sons; all daughters become carriers. The male manifests the condition because the $Y$ chromosome cannot neutralize the abnormal $X$ gene.
    • Carrier Female: Transmits to $50\%$ of sons (who manifest) and $50\%$ of daughters (who become carriers).
  • Example: Hemophilia and $G6PD$ deficiency.

Genetic Mutations at the Molecular Level

• Point Mutations: Alteration in a single base pair.
  • Nonsense Mutation: Leads to a stop codon, terminating the protein sequence (e.g., $\beta$-thalassemia).
  • Missense Mutation: Changes a single amino acid (e.g., Sickle Cell Anemia, where Valine replaces Glutamic acid at the $6^{th}$ position of the $\beta$-globin chain).
• Deletions and Insertions:
  • Frameshift Mutation: Insertion or deletion of bases (not in multiples of $3$) that alters the reading frame, resulting in a completely different amino acid sequence.
  • Three Base Deletion/Insertion: Gain or loss of a single codon (multiples of $3$). The reading frame remains intact, but the protein lacks or gains one amino acid (e.g., Cystic Fibrosis: deletion of phenylalanine at position $508$ of the $CFTR$ gene).
• The Human Genome:
  • Size: $3.2$ billion base pairs.
  • Composition: $25\%$ Exons (encode genes); $75\%$ Introns (intergenic, non-encoding sequences).
  • Introns: Removed by RNA splicing during protein synthesis. Mutations here generally do not affect the final protein product.

Biochemical Mechanisms of Translation

• Autosomal Dominant Mechanism:
  • Loss of Function: Typically affects non-enzyme proteins.
    • Regulatory Proteins: e.g., $LDL$ receptors in Familial Hypercholesterolemia.
    • Structural Proteins: e.g., Fibrillin in Marfan's; Collagen in $EDS$; Spectrin/Ankyrin in Spherocytosis.
  • Gain of Function: Production of a new, toxic protein (e.g., Huntington’s Disease producing huntingtin).
  • Enzyme Note: $AD$ rarely involves enzymes because heterozygotes (producing half-levels) usually have enough enzyme to function normally.
• Autosomal Recessive Mechanism:
  • Enzyme Deficiency: The largest category of Mendelian disorders.
    • Accumulation (Gain): Toxic substance buildup (e.g., Galactose in Galactosemia; Phenylalanine in Phenylketonuria).
    • Product Deficiency (Loss): Loss of an end product (e.g., Melanin in Albinism).
    • Failure to Inactivate: e.g., $\alpha-1$ antitrypsin deficiency leading to increased neutrophil elastase, destroying lung/liver tissue.
  • Non-Enzyme Defects: e.g., Sickle Cell (Transport), Hemophilia (Hemostasis), Muscular Dystrophy (Structural/Dystrophin).

Selected Autosomal Dominant Disorders

• Marfan’s Syndrome:
  • Genetics: Mutation in $FBN1$ gene ($15q21.1$) encoding fibrillin-$1$. Decreased fibrillin causes unabated $TGF-\beta$ signaling.
  • Skeletal: Tall stature, arachnodactyly (spider fingers), dolichocephaly (long face), pectus excavatum/carinatum, scoliosis, hyperextensible joints.
  • Ocular: Bilateral ectopia lentis (displaced lens), severe myopia.
  • Cardiovascular: Mitral valve prolapse (ballooning degeneration), aortic dilatation, cystic medionecrosis, aortic dissection/rupture (major cause of death).
  • Anecdotes: Michael Phelps and Abraham Lincoln are suspected cases due to facial/skeletal features.
• Ehlers-Danlos Syndrome ($EDS$):
  • Defect: Collagen synthesis or structure.
  • Features: Skin laxity (Cutis Laxa), easy bruisability, and joint hypermobility.
• Familial Hypercholesterolemia:
  • Genetics: Mutation in $LDLR$ gene (Chromosome $19$).
  • Pathology: Loss of receptors leads to loss of the inhibitory mechanism for cholesterol production. Liver continues producing cholesterol despite high blood levels. Results in premature atherosclerosis, xanthomas, and xanthelasmas.
• Neurofibromatosis ($NF$):
  • Type 1 (Von Recklinghausen): Mutation on $17q11.2$ ($NF1$ gene). Loss of neurofibromin (inhibitor of $RAS$). Features: Multiples skin nodules, Café-au-lait spots (over $6$ spots, $>15\,mm$ after puberty), Lisch nodules (pigmented iris clumps).
  • Type 2: Mutation on $22q12$ ($NF2$ gene). Loss of Merlin. Features: Bilateral vestibular schwannomas ($CN\,VIII$), tinnitus, hearing loss. No Lisch nodules.

Selected Autosomal Recessive Disorders

• Albinism: Deficiency of tyrosinase; no melanin. Increased risk of sun-induced skin cancers and solar keratosis.
• Alkaptonuria (Ochronosis): Lack of homogentisic oxidase. Homogentisic acid turns urine black when exposed to air and binds to cartilage, staining ear lobes blue-black and causing brittle cartilage/degenerative arthropathy.
• Lysosomal Storage Diseases ($LSD$):
  • Glycogenosis:
    • Von Gierke (Type I): Glucose-$6$-phosphatase deficiency. Hepatomegaly, renalomegaly, hypoglycemia.
    • McArdle (Type V): Muscle phosphorylase deficiency. Painful muscle cramps after exercise.
    • Pompe (Type III in transcript; usually II elsewhere): $\alpha$-Glucosidase deficiency. Massive cardiomegaly, heart failure within $2$ years.
  • Mucopolysaccharidoses ($MPS$): GAG accumulation. Hurler’s and Hunter’s syndromes. Coarse features, corneal clouding.
  • Sphingolipidoses:
    • Tay-Sachs: Hexosaminidase deficiency; ganglioside accumulation. Cherry red spot on macula; massive ballooned neurons; death by age $3$.
    • Niemann-Pick: Sphingomyelinase deficiency ($Type\,A/B$) or cholesterol transport defect ($Type\,C$). Spleen/liver enlargement. Foamy cells (RES, lungs, GIT).
    • Gaucher’s: Glucocerebrosidase deficiency. Most common $LSD$. Gaucher cells have a "crumpled tissue paper" appearance. Bone changes (Erlenmeyer flask deformity/widening of femoral neck).

Non-Classical Inheritance Patterns

• Trinucleotide Repeat Mutations ($TRM$):
  • Anticipation: Symptoms become more severe and appear earlier in subsequent generations as the number of repeats expands ($<10$ to $>1,000$).
  • Fragile X Syndrome ($FXS$): $CGG$ repeats in the $UTR$ of the $FMR1$ gene ($X$ chromosome). Expansion occurs during oogenesis. Clinical: Mental retardation, macroorchidism, long face with large mandible.
  • Huntington’s Chorea: $CAG$ repeats. Expansion occurs during spermatogenesis. Features: Progressive movement disorder and dementia.
• Mitochondrial Inheritance: Transmission exclusively through females (ova contains mitochondria; sperm does not). All children of an affected female are affected; children of an affected male are not.
• Genomic Imprinting: One copy of a gene is methylated (silenced) depending on parent-of-origin.
  • Prader-Willi Syndrome: Paternal deletion on Chromosome $15$ ($q11-13$). Obesity, hypotonia, hypogonadism.
  • Angelman Syndrome: Maternal deletion on Chromosome $15$ ($q11-13$). "Happy Puppets": Inappropriate laughter, seizures, hand-flapping.

Questions & Discussion

• Q: What characterizes Angelman syndrome?
• A: Maternal deletion of $15q11–q13$, resulting in intellectual delay, ataxia, and inappropriate laughter.
• Q: Differentiation between NF1 and NF2?
• A: $NF1$ ($Chr\,17$) has neurofibromas and Lisch nodules. $NF2$ ($Chr\,22$) features bilateral acoustic schwannomas and lacks skin nodules/Lisch nodules.
• Q: What is the "crumpled tissue paper" cell?
• A: The Gaucher cell, which is an enlarged macrophage seen in Gaucher’s disease due to glucocerebroside accumulation.
• Q: Inheritance of Turner Syndrome (45, XO)?
• A: Can occur via meiotic nondisjunction (classic) or mitotic nondisjunction (mosaic). Negative Barr bodies help in diagnosis.
• Q: Significance of PCR in single-gene disorders?
• A: While used for cancer and infectious diseases (e.g., COVID), it allows for synthesis and amplification of DNA fragments for identification of mutations.