genetic diseases

Sickle cell

Mutation in beta chain causing glutamate to valproate leading to hemolysis, U.N. crystallization (microvascular occlusion), tissue damage = plieotropy

Clinical features of sickle cell

Hyperbilirubin, reticulocytosis, irreversible sickle cell

Progeria

Sporadic autosomal dominant, Latin A (progestin) causes abnormal nuclear envelope, cellular accumulations, abnormal aging

Progeria clinical features

Skin and skeletal defects, arteriosclerosis, cardiovascular abnormalities

Cystic fibrosis

Most lethal inherited disease in caucasians, mutation in CFTR, autosomal recessive, decreased Cl transport, increased Na absorption, increased water absorption, decreased ciliary clearance

CF gastric symptoms

Abdominal distention, intestinal obstruction, increased frequency of stool, failure to thrive, flatulence, recurrent abdominal pain, jaundice, GI bleeding

CF respiratory symptoms

Cough, recurrent wheezing, recurrent pneumonia, atypical asthma, dyspnea, chest pain

CF genitourinary symptoms

Undescended testicles, hydrocele, delayed sexual development, amenorrhea

Mechanism of MODY

Mutation in HNF4A, degradation of mutated transcripts, defective pancreas beta cell function, no insulin

DM 2 mechanism

Mutation in PPAR alpha, ABCCC8, KCNJ11, defective insulin secretion/sensitivity

Ribosomopathies

Ribosomal haploinsufficiency, disrupted biogenesis, accumulation of free eibosomal proteins, bind to MDM2, activate p53, apoptosis, anemia

Leukemia

MiRNA overexpression, dysregulation of cell cycle associated genes, leukemia

What gene is overexpressed in lymphoma and leukemia

MiR-17-92

Hemophilia

Transposing insertion, mutation in factor 8, excess bleeding (clotting disorder)

Conditions caused by transposon

Hemophilia, neurofibromatosis, and breast/ovarian cancer from BRCA2

Charcot Marie tooth disease

Peripheral neuropathy, commonly inherited, tRNA mutation, defect in neuronal symptoms, myelin sheath and axonal damage

Charcot Marie tooth symptoms

Loss of muscle in legs, ankles, and feet, curled toes, decreased ability to run, foot drop, gait change, frequent tripping, decreased sensation in legs and feet, dominant X linked or autosomal recessive

Huntington disease

Mutation in Huntingin causing more CAG repeats on p arm, over 27 = increased anticipation, involuntary and abnormal movements (Huntington chorea)

Diamond blackfan anemia

Ribosomopathy, hypoproductive anemia with macrocytosis in first year, sporadic mutation, bone marrow is normocellular with reduced erythrocyte precursors, increased HbF, increased EPO, increased erythrocyte ADA, mutation in RPS19 and 24 causing impaired pre-rRNA processing of 18s rRNA (reduced ribosomal subunit), corticosteroids work

Diamond nonhaematological symptoms

Short stature, craniofacial, skeletal, and urogenital abnormalities, increases AML and osteogenic sarcoma

5q minus syndrome

Ribosomopathy, deletion of 5q which blocks erythrocyte differentiation decreased 40s ribosome and erythropoiesis, treated by lenalidomide which increases erythropiesis, corticosteroids not helpful

5q minus signs

Severe macrocytic anemia, normal/elevated platelets with hypolobulated micromegakaryocytes (platelets are small) and relatively low rate of progression of AML

Xeroderma pigmentosum

Defective ner, unrepaired UV induced mutations, xeoderma, predisposition to skin cancer

Hereditary non polyposis colorectal cancer

Autosomal dominant involved with dna mismatch repair, develop adenomas at same rate as public but more likely to progress to cancer

Severe combined immunodeficiency

X linked or autosomal recessive, mutation in common gamma chain which is a shared receptor for interleukins, most severe has defective non homologous dna end joining

Bloom syndrome

Mutation in blm, defective recQ helicases, defective dna unwinding, defective dna repair

Bloom syndrome signs

Butterfly rash, high pitched voice, long narrow face, prominent nose and ears

UV radiation

Break covalent between pyrimidines

High energy radiation

Break dna strands

Penetrance

Probability that a person who has a mutant allele will express the phenotype

Neurofibromatosis type 1

Autosomal dominant, develop benign and malignant tumors, mutation in neurofibromin (usually tumor suppressor) which originate from nonmyelinating Schwann cells

Duchenne muscular dystrophy

Mutation in the dystrophin gene (molecular shock absorber), X linked recessive, degeneration of muscle, elevated CPK correlate with degree of deterioration

Base excision

Uses specific dna glycosylase to cleave sugar base bond, fixes single base modification, available throughout cell cycle

DNA mismatch repair

Repairs, insertions, deletions, mis incorporations, during dna replication and recombination

Non homologous

Use dna ligase 4 to rejoin broken ends, mostly G1 but always available

Homologous repair

S and G2

Ner

G1 but not restricted