Pharmacogenetics Ch. 12

Monogenic diseases

Ch. 19

Monogenic diseases

• Aberations of a single gene

• Inheritance dominant or recesive (autosomal or sex chromosome)

• Examples:

– Huntington

– Myotonic dystrophy

– Neurofibromatosis

– Marfan syndrom

– Cystic fibrosis

– Duchenne muscular dystrophy

– Hemophilia

Huntington disease • 4p16 (Huntingtin, 1:10000), autosomal dominant with anticipation

• ↑ 40 polyglutamin (CAG ) repeats in 5’translated region

• Accumulation of huntingtin in neuronal aggregates - apoptosis

Preogressive movement disorder (chorea = involuntary movements); cognitive deterioration, possible dementia, psychiatric disorders

Myotonic distrophy (MD) • 19q13 (3’UTR of DMPK mRNA), 50-2000 x CTG

• autosomal dominant with anticipation (1:8000)

• Interference with cellular processing of RNA

gain of function for binding CUG-BP

• Weakness and myotonia, progressive spasm with prolonged relaxation, cataract, cardiac conduct defects, …

• More distal mucles affected,

also digestive tract

Typ 2 MD

• 3q21 (ZNF9), 75-11000 x CCTG

• Proximal myotonic myopathy

Neurofibromatosis • Mutation in NF gene (1 and 2) (17q11, neurofibromin, 1:3000)

• Autosomal dominant inheritance or de novo mutation (50%)

• Deletions, insertions, duplications and point substitutions: → truncaton or absence of tumor supressor neurofibromin protein

• Neurofibroms (benigne skin tumors), „cafe au lait” spots“, rarely mild mental retardation

• Possible epilepsy, CNS tumors, scoliosis

Marfan syndrom

• Mutation in FBN1 (fibrillin type 1, 15q21)

• Autosomal dominant inheritance

• Fibrillin forms elastic fibers in connective tissue

• High stature, arachnodactylia, weeknes and flexibility of joints, underweight, thoracic deformation, scoliosis, lens ectopy, possibility of aortal dissection

Cystic fibrosis • Mutation in CF gene(7q31) – cloride chanal

• Autosomal recessive trait (1: 2000 !)

• deletion (Phe508del), missense, frameshift, splicesite, nonsense,…

• “mucoviscidosis”- viscous secretion accumulation in lungs and pancreatic ducts, secundar cor pulmonale development

• complications: ileus, prolaps of rectum, infertility in males, cyrosis, diabetes

• Therapy: antibiotics, pulmonary drainage

Duchene – muscular dystrophy • The most common and severest

type of distrophy (1: 3500 mail)

• X linked recessive trait

• Mutation in Xp21 (distrophin gene)

• Symptoms in early childhood: progressive muscle weekness, lumbal lordosis, pseudohypertrophy of calves, joints contractures

• Letal in early adolthood (usualy no offsprings)

• Woman carrier detection – serum creatine kinase measurement and genotypinga

Hemophilia • Hemofilia: A (1: 5000), B rare – X linked recessive trait

• coagulation factor 8 defficite (less than 1%)

• Mild to severe bleeding, joint hemorrhage

• Therapy: coagulation factor substitution by transfusions

• Gene therapy candidates

1819-1901.