Diseases and Mutations Flashcards by Meaghan Fox

Chromsome for NF1

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Mode of Inheritance: Autosomal Dominant
Defective gene:- loss of function mutations of NF1 gene, neurofibromin
chromosome 17
disorder of nervous system
Phenotype: eyes (lisch nodules/multiple iris hamartomas), skeleton, skin (café au lait spots), benign and malignant tumors of nervous system,
Pleiotropic - variable expressivity -allelic heterogeneity - Signs develop during childhood
Affects tumor suppressor protein Ras GTPase

Neurofibromatosis (NF1)

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Chromosome for Achondroplasia?

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Defective gene for Achondroplasia?

FGFR3

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Mode of Inheritance: Autosomal Dominant, gain of function
Defective gene: Mutation in fibroblast growth factor receptor 3 gene (FGFR3)
Chromosome 4
Most common mutation is in Guanine at position 1,138
Phenotype: Small stature, short limbs, large head, low nasal bridge, prominent forehead, lumbar lordosis
new gain-of-function mutation

Achondroplasia

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Mode of Inheritance: Autosomal Dominant
Cutaneous xanthomas, premature coronary artery disease, high blood cholesterol levels
mutation in Low-Density Lipoprotein (LDL) receptor

Familial Hyperchoesterolemia

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Mode of Inheritance: Autosomal Dominant
Defective Gene: mutation in PKD1 (chromosome 16) and PKD2 (chromosome 4)
cyst development requires “two-hit” mechanism, both alleles of either PKD1 or PKD2 must lose function for cysts to form
Progressive renal failure, renal and hepatic cysts, intracranial saccular aneurysms, mitral valve prolapse, colonic diverticula

Polycystic Kidney Disease

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Chromsome for Marfan’s

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Defective gene for Marfan’s?

FBN1

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Mode of Inheritance: Autosomal Dominant
Phenotype: Disproportionate tall stature and skeletal abnormalities, hypermobile joints, ocular abnormalities (detached lenses), cardiovascular diseases, aortic rupture
Defective gene: Mutation in the FBN1 gene coding for fibrillin-1 - chromosome 15

Marfan’s Syndrome

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Mode of Inheritance: X-linked Recessive
Phenotype: blood fails to clot normally, bleeding into soft tissues, muscles, and weight bearing joints
Defective gene: Due to deficiency of factor VIII (F8) gene
incidence is 1 in 5000-10000 newborn males

Hemophilia A

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Mode of Inheritance: X-linked Recessive
Phenotype: blood fails to clot normally, bleeding into soft tissues, muscles, and weight bearing joints
Defective gene: Due to deficiency in factor IX (F9) gene
incidence is rare at 1 in 100000

Hemophilia B

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Mode of Inheritance: X-linked recessive
Phenotype: progressive myopathy
Defective gene: deletion of dystrophin gene
Frequently due to de novo mutations of large deletions (60-65%) and duplications, or small deletions, insertions or nucleotide changes

Duchenne Muscular Dystrophy (DMD)

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Mode of Inheritance: X-linked Dominant
normal prenatal and neonatal growth and development followed by rapid onset of neurological symptoms and loss of milestones between 6 mos and 18 mos of age
Phenotype: spastic, ataxic, autistic features, irritable behavior, purposeless flapping movements, seizures (50%)
patients become severely retarded
Defective gene: mutation in MECP2, methyl-CpG-binding protein 2, which mediates transcriptional silencing

Rett Syndrome

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Defective gene: mutation in MECP2, methyl-CpG-binding protein 2, which mediates transcriptional silencing

Rett Syndrome

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Chromsome for Huntington’s

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Mode of inheritance: Autosomal Dominant
Progressive disorder: motor: chorea and dystonia (involuntary movements and spasms), cognitive, and psychiatric changes
Age of onset about 35-44 yrs
Defective gene:Caused by an expanded polyglutamin repeat in the protein Huntington (Htt) causing protein to aggregate and damage neurons
Expansion of CAG trinucleotide repeats in Htt
Chromosome 4p16.3
CAG codes for glutamine, normal 40 CAG repeats

Huntington Disease

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Defective gene: Caused by abnormal CGG repeat >200 leading to hyper-methylation of 5’ UTR and decreased FMR1 (Fragile X Mental Retardation 1) expression

Fragile X Syndrome

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Mode of inheritance: X-linked Dominant
Phenotype: Big ears, big upper jaw, mental retardation and macroorchidism and deep plantar creases
Defective gene: Caused by abnormal CGG repeat >200 leading to hyper-methylation of 5’ UTR and decreased FMR1 (Fragile X Mental Retardation 1) expression

Fragile X Syndrome

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Chromsome for Myotonic Dystrophy-

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Defective gene: DMPK (dystrophia myotonica-protein kinase) gene undergoes repeat expansion of CUG triplet in the 3’ UTR of the mRNA

Myotonic Dystrophy

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Mode of inheritance: Autosomal Dominant
notorious lack of penetrance, pleiotropy, and variable expression in clinical severity and age of onset
phenotype: distal weakness and wasting, facial weakness, myotonia, cataracts, heart issues, GI issues, respiratory muscle issues, mental retardation, diabetes, hypogonadism
Defective gene: DMPK (dystrophia myotonica-protein kinase) gene undergoes repeat expansion of CUG triplet in the 3’ UTR of the mRNA
Chromosome 19

Myotonic Dystrophy

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Chromsome for Friedreich Ataxis

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Defective gene: due to GAA repeat expansion of 100-1,200 in the first intron of Frataxin gene impairing transcriptional elongation

Friedreich Ataxia (FRDA)

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- Mode of Inheritance: Autosomal recessive - incoordination of limb movements, difficulty with speech, diminished/absent tendon reflexes, cardiomyopathy, scoliosis, foot deformities - Defective gene: due to GAA repeat expansion of 100-1,200 in the first intron of Frataxin gene impairing transcriptional elongation - chromosome 9

Friedreich Ataxia (FRDA)

- Defective gene: mutations in 1 or more of RET (receptor tyrosine kinase), RET ligand GDNF (glial cell line-derived neurotrophic factor), EDNRB (endothelin B receptor) and its ligand endothelin3 (EDN3)

Hirschsprung Disease (HSCR)

- Mode of possible Inheritance: Autosomal Dominant (LOF), recessive, and multifactorial - Complete absence of some or all of the intrinsic ganglion cells in the colon - severe constipation, megacolon - Defective gene: mutations in 1 or more of RET (receptor tyrosine kinase), RET ligand GDNF (glial cell line-derived neurotrophic factor), EDNRB (endothelin B receptor) and its ligand endothelin3 (EDN3) - chromosome 10q11.2, 3p21, and 19q12

Hirschsprung Disease (HSCR)

- Autoimmune destruction of islet Beta cells in pancreas - Loss of insulin production - usually manifests in children or adolescence - polydipsia, polyuria - a genetic factor is MHC class II locus (HLA-DR3 or HLA-DR4) - DQB10201 allele (DR3) or DQB10302 allele (DR4)

Type 1 Diabetes Mellitus

- Late onset after age 60 - protein misfolding of Amyloid Precursor Protein (APP) creating neurotoxic peptide (AB1-42) - loss of memory, dementia, mood swings, B-amyloid neuritic plaques, neurofibrillary tangles, abnormal cleavage of amyloid precursor protein by alpha, beta, gamma secretases - Tau protein normally organizes microtubules but abnormal post-translation hyperphosphorylation causes tangles - ApoE (apolipoprotein E-involved in cearing LDL from the liver) gene disfunction [chromosome 19] e4 allele

Alzheimer Disease

-failure of fusion of the arches of the vertebrae with varying degrees of severity, typically in lumbar region

Spina bifida

- most common congenital malformation - failure of fusion of the frontal process with maxillary process - maternal smoking is a known risk factor

Cleft Lip and Palate

- genetic and environmental factors - males have a higher risk - hypertension, obesity, and diabetes mellitus are risk factors - environment factors are diet, physical activity, and smoking - obstruction of arteries feeding the heart - kills about 450,000 people in the US yearly

Coronary Artery Disease (CAD)

- symptoms include fever, difficulty breathing, productive cough with greenish sputum - history of recurrent lower respiratory tract infections and foul smelling diarrhea - mild cyanosis, tachycardia, clubbing of fingernails - high sweat sodium and chloride concentrations in sweat test - Defective gene: Caused by autosomal recessive mutation in CFTR gene (deltaF508): a deletion of phenylalanine at position 508 leading to inability of protein to escape the ER - inability of cells to transport chloride and water to body secretions (lung, pancreas, sweat glands) - Modifier genes: Mannose-Binding Lectin (MBL2) - plasma protein in innate immune system aiding in destruction of pathogenic organisms Transforming Growth Factor B1 (TGFB1) - promotes lung scarring and fibrosis after inflammation - chromosome 7q31-7q32

Cystic Fibrosis

- IgG antibodies produced by the mother Rh- mother pass through the placenta and attack the RBCs of the Rh+ fetus causing hemolysis - Treatment by injection of anti-Rh antibodies (Rho(D) immune globulin or RhoGAM) to destroy the fetal erythrocytes in her blood

Hemolytic Disease of the Newborn

- autosomal recessive - iron overload - mutant HFE gene in linkage disequilibrium with HLA-A\*0301

Hemochromatosis

I = q^2

Autosomal Recessive (HWeq)

2q = I

Autosomal Dominant (HWeq)

I = q I = affected males

X-linked Recessive (HWeq)

- autosomal recessive - post-axial polydactyly, congenital heart defects, prenatal tooth eruption, fingernail dysplasia, short-limbed dwarfism, short ribs, cleft palate, malformation of the wrist bones

Ellis-van Creveld (EVC) syndrome

- loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. As a result of the loss of genetic variation, the new population may be distinctively different, both genetically and phenotypically, from the parent population from which it is derived.

Founder Effect

- chronic inflammatory disease of the gastrointestinal tract - primarily adolescents and young adults - Crohn disease (IBD1 locus linkage) and ulcerative colitis are 2 major categories - NOD2 protein (nucleotide-binding oligomerization domain containing 2) gene- binds to gram-negative bacterial cell walls and participates in the inflammatory response to bacteria by activating the NF-κB transcription factor in mononuclear leukocytes; variants reduced ability of NOD2 to activate NF-κB leading to an abnormal inflammatory response

Inflammatory Bowel Disease (IBD)

- nocturnal abdominal pain, diarrhea, gradual weight loss - usually ileum and ascending colon - granulomatous inflammation causing narrowing and scarring - arthritis of spine and joints, uveitis, skin issues, hypercoagulability, erythema nodosum - treatment by corticosteroids, anti-inflammatory meds, antibiotics, immune modulators -presents in adolescence or young adulthood

Crohn Disease (CD)

- Defective gene: missense mutation in the 6th codon of the beta globin gene - glutamate to valine missense - hemoglobin with 2 normal alpha chains and 2 mutant beta chains (HbS) - causes HbS hemoglobin to polymerize under deoxygenated condtions - anemia, failure to thrive, splenomegaly, repeated infections, and dactylitis

Sickle Cell Anemia

- Mode of Anticancer: Autosomal Dominant - unstable hemoglobin with substitution of conserved phenylalanine with serine - heme drops out of pocket, hemoglobin precipitates, low oxygen affinity, cyanosis

Hb Hammersmith

- Mode of Inheritance: autosomal recessive - b-chain has a substitution at sixth amino acid from glutamic acid to lysine - less soluble than Hb A, tends to crystallize in RBCs causing hemolysis

Hb C

- Mode of Inheritance: Autosomal Dominant - His92 to Tyr - oxidized heme iron incapable of reversible oxygenation - cyanotic

Hb Hyde Park (a Hb M)

- Mode of Inheritance: Autosomal Dominant - Asp99 to Asn - locks hemoglobin into relaxed structure with high oxygen affinity - polycythemia

Hb Kempsey

- disorder of alpha-globin production (chromosome 16) - Hydrops fetalis- no alpha globin chains with high levels of Hb Bart's (gamma globin tetramer = ineffective) - Hb H - (4 beta subunits) loss of 3 alpha globin genes - severe anemia, splenomegaly - alpha - thalassemia trait - 2 functional alpha genes - mild anemia and microcytosis - ZF deletion of alpha1-globin gene at 3' end of LUC7L gene leading to antisense alpha2-globin RNA causing hypermethylation and thus gene silencing

alpha - Thalassemia disorders

- single-base pair substitution/point mutation - severe anemia (Cooley's anemia/thalassemia major) in B0 - B0 = no Hb A present - B+ = 10 to 30% Hb A detectable - hypochromic anemia, microcytic RBCs in B+ - chipmunk face

beta - Thalassemia

a benign condition because the remaining g gene or genes remain active after birth and Hb F (a2g2) compensates for the absence of Hb A

Hereditary Persistence of Fetal Hemoglobin (HPFH)

- Autosomal Recessive - (GM2gangliosidosis)-neurological degenerative disorder that develops at 6 months of age - Has increased frequency in certain genetic isolates such as Ashkenazi Jews in North America where the carrier frequency is 1 in 30.

Tay Sach's Disease

- Impairs the production of - Mostly due to point mutations in the β-globin - Lead to a decrease in the abundance of b-globin mRNA -Nonfunctional mRNAs - have premature stop codons (Gln39Stop) or single-base pair deletion at codon 16 → cause b0 thalassemia -Capping effect -Polyadenylation defect

Simple b-Thalassemia

- Locus Heterogeneity -Digenic inheritance - Disease phenotype requires that the affected individual is heterozygous for two rare mutations in two different unlinked genes without the influence of any known environmental factors - Mutant in both: Rom1 and Peripherin - Mutations in 43 different loci - Phenotype requires that the affected individual is heterozygous for 2 rare mutations in 2 different unlinked genes without the influence of any known environmental factors - Having the two mutated genes is sufficient to cross a threshold of cell damage, photoreceptor death, loss of vision - Hetero patients for both the Rom1 and Peripherinphotoreceptor membrane proteins will develop the disease

Retinitis Pigmentosa

- Missense mutation in Factor V Leiden, FVL, at position 506: Arg→Gln(protein more stable) - Missense: A.A. → Different Amino Acid -Mutations in 3’ UTR 20210 G\>A, stabilizes the mRNA (\*\*Purine Transition) AND Increase in Oral Contraceptives affect Prothrombin -Oral Contraceptives affect factor 10 -Hyper-coagulable state: venous or arterial clots form inappropriately and cause life-threatening complications. - mutations are also involved with deep venous thrombosis of the lower extremities seen in 1 per 1,000 individuals per year with mortality of up to 10% primarily due to pulmonary embolus, depending on age and the presence of other medical conditions

Idiopathic Cerebral Vein Thrombosis

the forebrain, overlying meninges, vault of skull and skin are absent → most infants are still born and 2/3 of affected infants are female

anencephaly

gain of function mutation that results in unregulated hyperfunction of the kinase which leads to dominantly inherited cancer of the thyroid and adrenal glands -chromosome 10 -RET gene

Multiple endocrine neoplasia (MEN) type 2a and 2b

-thought to regulate several intracellular processes, including activating Ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor -it is widely expressed in almost all tissues, but most abundantly in the brain, spinal cord, and peripheral nervous system

Neurofibromin

-pseudoautosomal inheritance -dominantly inherited skeletal dysplasia with a disproportionate short stature and deformity of the forearm -caused by mutation in the SHOX gene (which escapes x-inactivation)

Dyschondrosteosis

a condition marked by the deposit of bile pigments of the brain and spinal cord by degeneration of nerve cells that occurs usually in infants as part of the syndrome of erythroblastosis fetalis

Kernicterus

an inflammatory disorder that involves tender, red bumps under the skin

erythema nodosum

a condition that causes large, painful sores to develop on skin

pyoderma gangrenosum

chronic liver disease caused by progressive inflammation ad scarring of the bile ducts of the liver. the inflammation impedes bile flow to the gut, which can lead to cirrhosis, liver failure and cancer.

primary sclerosing cholangitis

sickle cell hemoglobin due to single missense nucleotide substitution changes the codon of the 6th amino acid from glutamic acid to valine

Hb S

mode of inheritance for Neurofibromatosis (NF1)

Autosomal Dominant

mode of inheritance for Achondroplasia

Autosomal Dominant, gain of function

mode of inheritance for Familial Hyperchoesterolemia

autosomal Dominant

mode of inheritance for Polycystic Kidney Disease

- Autosomal Dominant

mode of inheritance for Marfan's Syndrome

-Autosomal Dominant

mode of inheritance for Hemophilia A

-X-linked Recessive -

mode of inheritance for Hemophilia B

- X-linked Recessive -

mode of inheritance for Duchenne Muscular Dystrophy (DMD)

X-linked recessive -

mode of inheritance for Rett Syndrome

:X-linked Dominant -

mode of inheritance for Huntington Disease

- Autosomal Dominant

mode of inheritance for Fragile X Syndrome

X-linked Dominant -

mode of inheritance for Myotonic Dystrophy

Autosomal Dominant -

mode of inheritance for Friedreich Ataxia (FRDA)

-Autosomal recessive

Hemolytic Disease of the Newborn

Hemochromatosis

- autosomal recessive - iron overload -mutant HFE gene in linkage disequilibrium with HLA-A\*0301

Autosomal Recessive (HWeq)

I = q^2

Autosomal Dominant (HWeq)

2q = I

X-linked Recessive (HWeq)

I = q I = affected males

mode of inheritance for Ellis-van Creveld (EVC) syndrome

- autosomal recessive -

mode of inheritance for Hb Hammersmith

-Autosomal Dominant

mode of inheritance for Hb C

- autosomal recessive -

mode of inheritance for Hb Hyde Park (a Hb M)

-Autosomal Dominant -

mode of inheritance for Hb Kempsey

Autosomal Dominant

mode of inheritance for Tay Sach's Disease

-Autosomal Recessive

Defective Gene: FGRF3?

Acondroplasia

Defective Gene: FBN1?

Marfan's

Factor 8?

Hemophilia A

Factor 9?

Hemophilia B

Expansion repeats in Huntington's?

Expansion of CAG trinucleotide repeats

Repeat Expansion for Myotinic Dystrophy?

undergoes repeat expansion of CUG triplet in the 3' UTR of the mRNA

Repeat Expansion for Friedrich Ataxia?

GAA repeat expansion of 100-1,200 in the first intron of Frataxin gene impairing transcriptional elongation

What is the mode of inheritance for Sickle Cell Anemia?

What causes the sickle cell hemoglobin?

a single missense nucleotide substitution change in the codon of the 6th amino acid from glutamic acid -\> valine

anemia, failure to thrive, splenomegaly leading to autosplenectomy, dactylitis

sickle cell

B-chain has substitution at 6th amino acid from glutamic acid-\> lysine -less soluble than HbA and tends to crystallize in RBCs causling a mild hemolytic disorder

Hb C

unstable hemoglobin with substitution of the Phe42 with Ser, allowing heme to drop out of the pocket, causing hemoglobin to precipate -low oxygen affinity leads to cyanosis

Hb Hammersmith

His92Tyr - b-chain methemoglobin wehre oxidized heme iron is incapcable of reversible oxygenation - cyanosis

Hb Hyde Park

Aps99Asn -mutation "locks" hemoglobin into the relaxed structure with high oxygen affinity causing polycythemia (increase in RBC #)

Hb Kempsey

What are Heinz bodies, how do they form, and what do they do?

In Thalaseemias, the chin produced at the normal rate is in excess and eventually precipitates to form these occlusions, which damage the membrane and cause premature RBC destruction.

all 4 a-globin chains are absent - high levels of Hb Barts - severe intrauterine hypoxia, stillbirth ot neonatal death

Hydrops fetalis

homotetrameric with g4 composition is an ineffective oxygen carrier, primarily seen among Southeast Asians

Hb Barts

loss of 3 a-genes -moderately severe anemia and splenomegaly

Hb H

functional a genes (a-/a- or aa/--) mild anemia, microcytosis

a-thalassemia trait two

What causes the most common form of a-thalasseia?

deletions of one of the two a-globin genes on a chromosome

What can cause the deletion of tha a-globin gene?

misalignment, homologous pairing, and recombination between the a1 gene on one chromosome and the a2 gene on the homologous chromosome

the mutation associated with the 13kb HpaI fragment of the sickle cell gene originated where?

West Africa

the mutation associated with the 7.6kb HpaI fragment of the sickle cell gene originated where?

it arose separately and probably had multiple origins

What does the Zf deletion remove?

the a1-globin gene and the 3'end of the LUC7L gene, including its termiantion site

What does the ZF deletion lead to?

formation of a mutant hybrid RNA composed of the LUC7L mRNA and an antisense a2-globin RNA

the antisense a1-globin RNA formed in the ZF deletion contains sequences that correspond to what?

a2-globin CPG island

the antisense transcription formed in the ZF deletion is consistently associated with what?

methylation of the q2-globin CPG island and silencing of the a2-globin gene expression

What is β-thalassemia usually due to?

single-base pair substitution (point mutation), not deletions

individuals with 2β-thalassemia alleles -severe anemia and need ligelong medical management

Thalassemia Major/Cooley's anemia

no HbA present

β0 thalassemia

only 10-30% of HbA detected

β+ thalassemia

seen in carriers of one β-thalassemia allele -hypochromic, microcytic RBCs, slight anemia

thalassemia minor

how is β-thalassemia treated?

bone marrow transplant

any type og anemai in which the red blood cells are paler than normal

hypochromic

what do the classic feature of **β-**thalassemia of prominent cheebones result from?

expansion of the marrow cavity in the bones of the skll and face

~80% of untreated β-thalassemia patients die by what age?

5 years

impairs the production of β-globin alone results in many differnt types of molecular abnormalitiels, predomianntly point mutaitons - most lead to a decrease in β-globin gene

Simple β-thalassemia

premature stop codons due to a single nucleotide substititution (Gln39Stop) or single base pair deletion at codon 16 that can lead to B0 thalassemia

Nonfunctional mRNAs

What is the capping defect?

patient had an A-\>C transversion

what is the polyadenlyation defect

signal AAUAAA, patient had substitution to AACAAA