Fundamentals of Molecular Medicine

Summary of disorders-Exam 1

1) Werner Syndrome

-Autosomal recessive.-Premature aging and retarded bone growth. -DNA repair is deficient .

2) Xeroderma pigmentosum

-Autosomal recessive.-Mutation of 7 out of 8 genes – Deficiency in Nucleotide Excision Repair (NER). Patients are unable to repair pyrimidine dimers.-Mutation in XP-V- Deficiency in translesion synthesis after UV damage.-Patients are photosensitive, have many freckles, eyes are sensitive to light, and are susceptible to skin cancers. Risk of skin cancer is 2,000 to 5,000 fold higher than general population.

3) Cockayne Syndrome

-Autosomal recessive-Defects in XP-B, XP-D or XP-G-Mutation in CSA or CSB.-Deficiency in transcription-coupled repair -Horse-riding stance, jerky movements, difficulty walking, short stature, and mental retardation.

4) Trichothiodystrophy

- Autosomal recessive - Congenital hair shaft disorder.- Defects in repair and transcription function of XP-B of XP-D.- -Short stature, photosensitivity, and intellectual impairment.

5) Bloom Syndrome

- Autosomal recessive.- Chromosomal instability.- Increased SCE.- Immune defects and sensitive to sunlight.- Extreme growth retardation.- Predisposition to leukemias, lymphomas and other tumors.- Deficient helicase.

6) Familial Breast Cancer

-Autosomal dominant.-Mutation in BRCA 1 and BRC2 tumor suppressors.

7) Ataxia telangiectasia

-Autosomal recessive.-Mutation in ATM gene.-Translocation 7q;14p.-Extreme radiation sensitivity.-Predisposition to tumors (lymphoma, leukemia).-Telangiectases.

8) Neurofibromatosis

-Mutation in NF1 gene.-Autosomal dominant.- COMPLETE PENETRANCE and VARIABLE EXPRESSIVITY.-Café au lait spots are characteristic.

9) Myotonic dystrophy

- Autosomal dominant- DM1- Trinucleotide repeat CTG in DMPK gene.- DM2- Tetranucleotide repeat CCTG in ZNF9 gene.- Anticipation.- Muscle contracts but cannot relax.

10) Huntington’s disease

- Autosomal dominant- CAG trinucleotide repeat, huntintin gene 4p16- Neurodegenerative -affects muscle coordination and leads to cognitive

decline and dementia.

11) Fragile X Syndrome

- X-linked- Trinucleotide repeat expansion CGG on X chromosome. CGG repeats

increase hypermethylation of promoter region that represses transcription of FMR1.

- Failure to express protein coded by FMR1 gene(DNA methylation=silencing, which is required for normal neural development).

FMR1 encodes a protein that regulates mRNAs important for normal neural development.

- Broad forehead, elongated face, large prominent ears, strabismus, mitral valve prolapse, hypotonia, enlarged testicles.

- MOST COMMON FORM OF INHERITED MENTAL RETARDATION.

12) Achondroplasia (dwarfness)

-G380R missense mutation

- Occurs as a de novo mutation in approximately 80% of cases (associated with advanced paternal age) or may be inherited as an autosomal dominant genetic disorder.

-Gain –of- function causing constitutive activation of FGFR3 inhibits growth.

13) Thanatophoric dysplasia

- Severe skeletal disorder characterized by a disproportionately small ribcage, extremely short limbs and folds of extra skin on the arms and legs.

- De novo mutation.

14) Beckwith-Wiedemann Syndrome

-Uniparental disomy-Maternal copy of 11p15 region is replaced with an extra paternal copy. -Extra IGF2 expression-Overgrowth disorder present at birth, characterized by an increase risk of childhood cancers.

15) Angelman syndrome

- Deletion or inactivation/imprinting of genes on the maternally inherited 15q11 (UBE3A).

- -Neurodegenerative disorder, developmental delay, sleep disturbances, jerky movements, frequent laughter, and a usually happy demeanor.

- Maternal chromosome is inactive (methylated)- maternal imprinting.

16) Prader-Willi Syndrome

-Same mutation as Angelman, but individuals are only affected if they inherit the mutation from the father

-Low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity.-Paternal chromosome is inactive (methylated) paternal imprinting.

17) Duchenne muscular dystrophy

-Recessive x-linked

18) Idiopathic chronic pancreatitis

-Leading cause of non-alcoholic pancreatitis.-10-40% individuals have a mutation in CFTR gene not associated with cystic fibrosis-20% have mutations in SPINK1 gene.

19) Retinitis pigmentosa

- Two mutations in different unlinked genes encoding for photoreceptor proteins (peripherin and Rom 1).

- Compound heterozygotes have both mutations and have the disease.- Heterozygotes for either one do not have the disease.

20) Chronic myelogenous leukemia (CML)

- Blood cells divide without differentiating terminally.- Translocation of tyrosine kinase abl. Reciprocal translocation between

chromosome 9 and 22.- Fusion of bcr/abl on chromosome 22- oncongene.- Fusion of bcr/abl- Philadelphia chromosome- Enhanced tyrosine kinase

activity that causes excess proliferation of myeloid cells.

21) Burkitt’s lymphoma

- 90% of cases- Translocation of c-myc from chromosome 8 to chromosome 14 (close to enhancers of antibody heavy chains).

- 10% of cases- c-myc (oncogene)-Translocated close to the antibody genes on chromosome 2 or 22.

- B-cells proliferate without terminally differentiating.

22) Familial adenomatous polyposis (FAP) (familial colon cancer)

- Adenomatous polyposis coli (APC- tumor suppressor) is mutated. - Continued Wnt singaling, cell cyle continues- transcription of Wnt

responsive genes.- Patients have benign polyps that can become cancerous.

23)- Rb-protein tumor suppressor is missing.

24) Down syndrome

-Trisomy 21.-Most common form of congenital mental impairment.-Single palmar crease, short fifth finger, flattened nose and face.

25) Edwards Syndrome

-Trisomy 18.-Small mouth and jaw, short neck, clenched hands with overlapping fingers, flexed big toe, and malformed ears.

26) Patau Syndrome-Trisomy 13. -Small head, cleft lip and/or palate, dysplastic or malformed ears.-Polydactyly.

27) Turner Syndrome

-X0-Short stature, poor breast development, no menstruation, widely spaced nipples, and shield-shaped thorax.-One of the most common chromosomal abnormalities in spontaneous abortions.-75% cases, the X chromosome is of maternal origin.-Variation: 18% of patients have an X isochromosome( 2 copies of the long arm (q) and missing the short arm (p)).

28) Klinefelter’s syndrome

-XXY-Poor beard growth, small testicles, wide hips, and breast development.-Most common cause of hypogonadism and infertility in males.- 53% of patients- extra chromosome is from paternal meiosis 1-34% patients- maternal meiosis I- 9%- maternal meiosis II3%- postzygotic errors.

29) DiGeorge Syndrome

-22q11 deletion.-Hypoparathyroidism- (Convulsions from hypocalcemia due to hypoparathyroidism).

-Thymic Hypoplasia (recurrent infections- T cell deficiency).-Heart defects (Tetralogy of Fallot).-Variable expressivity.

30) Cri-du-chat

-5p15 deletion-Dysmorphic facial features, microcephaly, low birth weight, severe retardation, congenital heart disease (septal defect), and cat-like cry.

31) Hirshprung disease (HSCR)

-1/5000 newborns, 2xM>F.-Defect of neural crest migration to the intestinal tract (aganglionic plexus).-Inability to defecate- abdominal distention.-Multiple genes associated in familial and sporadic cases, primarily RET.

32) Diabetes Miellitus

-Type I- Autoimmune destruction of pancreatic islet. (30% of patients are heterozygous for HLA-DQ2/DQ8).-Type II- Insulin resistance at the target cell.

33) Alzheimer’s Disease

-Most common degenerative disorder of the CNS-1st degree relative affected; 3-4x increases risk.-Mutations cause abnormal aggregation of amyloid plaques in neurons.

34) Li-Fraumeni

-p53 mutation.-Leads to different types of cancer in the same family.- Autosomal dominant.

35) Beta-thalassemia

- Beta += Intermediate amount of functional beta globin chains.- Beta zero- No functional beta globin chains.- Beta + = Mutation in TATA Box (A to G or A to C in the -28 to -32 region)

or point mutation that changes the sequence in the hnRNA at the polyadenylation site from AAUAAA to AACAAA

36) Systemic lupus erythematosus

-Autoimmune antibodies against U1 snRNPS.

-Chronic inflammation of body tissues and tissue damage.

37) Hutchinson-Gilford Progeria Syndrome

-90% cases are due to a change from GGC to GGT in codon 608 of lamin A gene.-Truncated lamin A with an internal deletion of 50 AA. This mutated lamin A accumulates farnesyl and obstructs the nuclear envelope, disrupting transcription and translation.

38) Sickle-cell anemia

- Missense mutation in Beta globin alleles - GAG to GTG in DNA, GUG in mRNA, glutamine to valine in protein.

39) Alpha thalassemia

-Deletion of 2, 3 or all 4 of alpha globin genes.-Abnormally long alpha globin molecules due to mutations in stop codon UAA via frameshift mutations or insertions (141 AA become 172 AA).

40) Hemoglobin Wayne

-Elongated alpha chain frameshift variant .-Lys-Tyr-Arg is replaced by Asx-Thr-Val-Lys-Leu-Glu-Pro-Arg octapeptide.

41) Prion disease

-A set of diseases called scrapie in sheep, Creutzfeldt-Jacob disease in humans, and bovine spongiform encephalopathy are caused by a misfolded and aggregated prion protein.-Mutated prion proteins can mutate healthy prion proteins when they come into contact.-Microscopic holes are characteristic of prion-affected tissue sections.