Genética y receptores NBME

Cystic Fibrosis

• Gene: CFTR (ΔF508 deletion), Chromosome 7

• Inheritance: Autosomal recessive

• Pathophysiology:

  • Mutation → misfolded CFTR protein → retained in RER, not transported to cell membrane.

  • Defective Cl⁻ channel →↑ Na⁺ and H₂O reabsorption→ thickened mucus → lung, pancreatic, GI dysfunction

• Clinical Features:

  • Neonatal: Meconium ileus

  • Pancreatic insufficiency: steatorrhea

  • Azoospermia (no vas deferens)

  • Recurrent infections: S. aureus (kids), Pseudomonas (adults)

• Diagnosis:

  • ↑ Cl⁻ in sweat test, immunoreactive trypsinogen (newborn screening)

• Treatment: CFTR modulators (ivacaftor, lumacaftor), Chest physiotherapy, pancreatic enzyme replacement,

Phenylketonuria (PKU)

• Gene: PAH (phenylalanine hydroxylase); cofactor: tetrahydrobiopterin (BH4)

• Inheritance: Autosomal recessive

• Pathophysiology:

  • Deficiency of PAH or BH4 → accumulation of phenylalanine → neurotoxic

• Clinical features:

  • Intellectual disability

  • Musty body odor

  • Hypopigmentation: fair skin, blue eyes

  • Seizures, eczema

• Treatment: ↓ phenylalanine (avoid aspartame), ↑ tyrosine, BH4 supplements

Friedreich Ataxia

• Gene: FXN (frataxin), Chromosome 9

• Mutation: GAA trinucleotide repeat (autosomal recessive)

• Pathophysiology:

  • ↓ Frataxin → mitochondrial dysfunction → oxidative stress and degeneration of neurons (dorsal columns, spinocerebellar tract)

• Clinical Features:

  • Childhood-onset progressive ataxia

  • Pes cavus, kyphoscoliosis

  • Hypertrophic cardiomyopathy (cause of death)

  • Diabetes mellitus

Kartagener Syndrome (Primary Ciliary Dyskinesia)

• Gene: DNAI1, DNAH5

• Inheritance: Autosomal recessive

• Pathophysiology:

  • Immotile cilia due to dynein arm defect

• Clinical features:

  • Chronic sinusitis, bronchiectasis

  • Situs inversus (50%)

  • Male infertility (immotile sperm), recurrent otitis media

Oculocutaneous Albinism (OCA)

• Genes:

  • TYR (type I), OCA2 (type II), TYRP1 (type III), SLC45A2 (type IV)

• Inheritance: Autosomal recessive

• Pathophysiology:

  • Deficient melanin biosynthesis in melanocytes

• Clinical features:

  • Reduced visual acuity, photophobia, nystagmus

  • ↑ risk of squamous cell carcinoma, melanoma

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

• Gene: PKD1 (Chr 16, ~85%), PKD2 (Chr 4, ~15%)

• Inheritance: Autosomal dominant

• Pathophysiology:

  • Cyst development in renal tubules → progressive kidney failure

• Clinical features:

  • Bilateral enlarged kidneys, hematuria, flank pain

  • Associated: berry aneurysms, mitral valve prolapse, hepatic cysts

  • ESRD usually by 50–60 y/o

Huntington Disease

• Gene: HTT (Huntingtin gene)

• Chromosome: 4

• Inheritance: Autosomal dominant, trinucleotide repeat (CAG)n with paternal anticipation

• Pathophysiology:

  • Accumulation of mutant huntingtin protein → neurotoxicity, especially in caudate nucleus and putamen (neostriatum)

  • ↓ GABA and ACh

• Clinical Features:

  • Chorea (involuntary movements)

  • Dementia and psychiatric changes (depression, aggression)

  • Atrophy of caudate and putamen (MRI: enlarged lateral ventricles)

  • Onset usually 30–50 y/o; progressive and fatal

• Mnemonic: “CAG = Caudate loses ACh and GABA”

Fragile X Syndrome

• Gene: FMR1 (fragile X mental retardation 1)

• Mutation: CGG trinucleotide repeat expansion → gene silencing by methylation

• Inheritance: X-linked dominant

• Pathophysiology:

  • Hypermethylation → ↓ expression of FMR1 → impaired synaptic plasticity

• Clinical Features:

  • 2ND Most common inherited cause of intellectual disability (1ST = DOWN SYNDROME)

  • Long face, large ears, macroorchidism

  • Autism spectrum behaviors, mitral valve prolapse

Marfan Syndrome

• Gene: FBN1 (Fibrillin-1), Chromosome 15

• Inheritance: Autosomal dominant

• Pathophysiology:

  • Defective microfibrils in connective tissue → Defective fibrillin → abnormal elastic fibers + ↑ TGF-β activity

• Clinical Features:

  • Tall stature, long limbs, arachnodactyly

  • Aortic root dilation → dissection, MVP

  • Ectopia lentis (lens dislocation upwards)

  • pectus deformities

Rett Syndrome

• Gene: MECP2 (X-linked mutation, de novo)

• Inheritance: Sporadic (girls only; lethal in males)

• Pathophysiology:

  • Loss of transcriptional repression during development

• Clinical Features:

  • Normal development then regression at 6–18 months

  • Hand-wringing, seizures, intellectual disability, scoliosis

Osteogenesis Imperfecta (Type I)

• Genes: COL1A1, COL1A2

• Inheritance: Autosomal dominant

• Pathophysiology:

  • ↓ type I collagen synthesis

• Clinical features:

  • Bone fractures with minimal trauma

  • Blue sclerae (translucent connective tissue)

  • Hearing loss (ossicle damage)

  • Dental imperfections

Mitochondrial Myopathies

• Genes: Mutations in mtDNA (maternal inheritance)

• Pathophysiology:

  • Defective oxidative phosphorylation → CNS + muscle symptoms

• Diseases:

  • MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes)

  • MERRF (myoclonic epilepsy with ragged red fibers)

  • LHON (Leber hereditary optic neuropathy): subacute vision loss in males

MELAS

• Gene: mtDNA (heteroplasmic mutation)

• Inheritance: Mitochondrial (maternal)

• Pathophysiology:

  • Defective oxidative phosphorylation

• Clinical features:

  • Myopathy

  • Encephalopathy

  • Lactic acidosis

  • Stroke-like episodes in young patients

Ehlers-Danlos Syndrome (EDS)

• Genes: Multiple, depending on subtype:

  • COL5A1, COL5A2 (classic type, AD)

  • COL3A1 (vascular type, AD)

• Inheritance: Autosomal dominant (some forms AR)

• Pathophysiology: Defects in collagen synthesis (mainly types III and V)

• Clinical features:

  • Hyperextensible skin

  • Joint hypermobility

  • Easy bruising, poor wound healing

  • Vascular type: risk of arterial rupture, organ rupture (esp. uterus, colon)

Tuberous Sclerosis

• Genes: TSC1 (hamartin, Chr 9), TSC2 (tuberin, Chr 16)

• Inheritance: Autosomal dominant with variable expressivity

• Pathophysiology: Tumor suppressor gene loss → ↑ mTOR signaling → hamartoma formation

• Clinical features:

  • Seizures, intellectual disability

  • Facial angiofibromas (adenoma sebaceum)

  • Shagreen patches, ash-leaf spots (hypopigmentation)

  • Renal angiomyolipomas

  • Cardiac rhabdomyomas

  • Subependymal giant cell astrocytomas (SEGAs)

Neurofibromatosis Type 1 (NF1 / von Recklinghausen disease)

• Gene: NF1 (neurofibromin, Chr 17)

• Inheritance: Autosomal dominant, 100% penetrance, variable expression

• Pathophysiology: Tumor suppressor gene → negative regulator of RAS

• Clinical features:

  • Café-au-lait macules

  • Neurofibromas (cutaneous and plexiform)

  • Axillary/inguinal freckling

  • Optic gliomas

  • Lisch nodules (iris hamartomas)

  • Risk of pheochromocytoma

Neurofibromatosis Type 2 (NF2)

• Gene: NF2 (merlin/schwannomin, Chr 22)

• Inheritance: Autosomal dominant

• Pathophysiology: Loss of tumor suppressor → CNS tumors

• Clinical features:

  • Bilateral vestibular schwannomas (hallmark)

  • Juvenile cataracts

  • Meningiomas, ependymomas

  • Hearing loss, balance dysfunction

Hemophilia A and B

• Genes:

  • A: F8 (Factor VIII)

  • B: F9 (Factor IX)

• Inheritance: X-linked recessive

• Pathophysiology: Coagulation factor deficiency → impaired intrinsic pathway

• Clinical features:

  • Hemarthroses (joint bleeding)

  • Easy bruising

  • Prolonged aPTT, normal PT/bleeding time

• Treatment: Factor replacement therapy

Duchenne Muscular Dystrophy (DMD)

• Gene: DMD (dystrophin); frameshift or nonsense mutation

• Inheritance: X-linked recessive

• Pathophysiology: Absence of dystrophin → sarcolemma instability → myonecrosis

• Clinical features:

  • Onset <5 y/o, rapid progression

  • Gowers sign (climb up legs)

  • Calf pseudohypertrophy (fat/fibrosis)

  • Elevated CK and aldolase

  • Dilated cardiomyopathy

• Death: by early adulthood (respiratory/cardiac failure)

Becker Muscular Dystrophy

• Gene: DMD (in-frame mutation)

• Inheritance: X-linked recessive

• Pathophysiology: Partially functional dystrophin protein

• Clinical features:

  • Later onset (adolescence/adulthood)

  • Milder weakness

  • Slower progression

  • Preserved lifespan relative to DMD

Alport Syndrome

• Gene: COL4A5 (most common, X-linked); less commonly COL4A3/4 (AR/AD)

• Inheritance:

  • X-linked dominant (classic)

  • Some forms AR/AD

• Pathophysiology: Defective type IV collagen in basement membranes

• Clinical features:

  • Glomerulonephritis → hematuria, progressive renal failure

  • Sensorineural deafness

  • Ocular findings (e.g., anterior lenticonus)

  • EM: “Basket-weave” appearance of GBM

Polygenic Inheritance

• Definition: Traits/diseases influenced by multiple genes and environmental factors; no single mutation explains causation.

• Inheritance pattern: Does not follow Mendelian rules; risk ↑ with more affected family members.

• Mechanism: Combined effect of multiple genetic loci with small individual effect sizes

Examples:

• Type 1 and 2 Diabetes Mellitus

• Hypertension

• Coronary artery disease

• Schizophrenia

• Bipolar disorder

• Autism spectrum disorders

• Psoriasis

• Multiple sclerosis

• Rheumatoid arthritis

• Alopecia areata

• Alzheimer’s disease

• Obesity

MEN 1, 2A, 2B

• ALL: AD

• MEN 1 = 3 P's: Parathyroid, Pituitary, Pancreas

  • Mutation: MEN1 (tumor suppressor)

  • Watch for kidney stones, ulcers, hypoglycemia

• MEN 2A = 2 P's + T: Parathyroid, Pheochromocytoma, Thyroid (medullary)

  • Mutation: RET (proto-oncogene)

  • Prophylactic thyroidectomy often in childhood

  • RET testing is mandatory in families

• MEN 2B = 1 P + T + M: Pheochromocytoma, Thyroid, Mucosal neuromas + Marfanoid

  • Mutation: RET (different codon)

  • No parathyroid involvement

  • Oral/intestinal neuromas + tall habitus

Intracellular Receptors

• Ligands:

  • Steroid hormones: cortisol, aldosterone, estrogen, progesterone, testosterone

  • T₃

  • Vitamin D (calcitriol)

  • Retinoic acid (vitamin A)

• Location: Cytoplasm or nucleus

• Mechanism:

  1. Lipophilic hormone crosses the cell membrane.

  2. Binds to a receptor in cytoplasm or nucleus.

  3. Hormone-receptor complex acts as a transcription factor → binds hormone response elements (HREs) in DNA → modulates gene expression.

• Example conditions:

  • Glucocorticoids modulate anti-inflammatory gene transcription.

  • Thyroid hormone upregulates metabolic gene expression.

Tyrosine Kinase Receptor

• Ligands:

  • Insulin

  • Growth factors: IGF-1, EGF, FGF, PDGF, VEGF

• Structure:

  • Single-pass transmembrane protein with intrinsic kinase activity.

• Mechanism:

  1. Ligand binds → receptor dimerizes.

  2. Autophosphorylation of intracellular tyrosine residues.

  3. Activates downstream signaling pathways:

     • RAS/MAPK → cell proliferation

     • PI3K/AKT → cell survival, metabolism

• Clinical relevance:

  • Target for monoclonal antibodies

  • Insulin RTK → upregulates GLUT4 in skeletal muscle/adipose

Non-Receptor Tyrosine Kinase (Cytoplasmic Tyrosine Kinase)

• Ligands:

  • Cytokines: IL-2, IL-6, IFN-α, IFN-γ

  • Hematopoietic factors: EPO, G-CSF, TPO

  • Hormones: GH, prolactin

• Associated pathway: JAK-STAT

• Mechanism:

  1. Ligand binds membrane receptor (no intrinsic kinase activity).

  2. JAK (Janus kinase) binds cytoplasmic domain.

  3. JAK phosphorylates STAT proteins.

  4. Phosphorylated STATs dimerize and enter nucleus → gene transcription.

• Mnemonic: “JAK for cytokines & growth hormones”

• Clinical correlation:

  • Ruxolitinib (JAK inhibitor) used for myeloproliferative disorders

G-Protein

1. Gs → ↑ cAMP → PKA activation

   1. examples:

      1. TSH → thyroid hormone synthesis

      2. PTH → bone resorption & renal Ca²⁺ reabsorption

      3. β₂ → bronchodilation:

2. Gi → ↓ cAMP → ↓ PKA

   1. effects:

      1. α₂ agonists (e.g., clonidine) → ↓ sympathetic outflow

      2. D₂ antagonists (antipsychotics) → ↑ prolactin (via pituitary disinhibition)

3. Gq → ↑ IP₃/DAG → ↑ PKC + Ca²⁺

   1. effects:

      1. α₁: smooth muscle contraction → ↑ BP

      2. M₃: glandular secretion

      3. Angiotensin II: vasoconstriction + aldosterone release

Pathway	Mnemonic	Key Examples
Gs	“FLAT ChAMP”	FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2), MSH, PTH
Gi	“MAD 2s”	M2, α2, D2
Gq	“HAVe 1 M&M”	H1, α1, V1, M1, M3