Patterns of Inheritance I and II

Question 1

define gene

Answer 1

• sequence of DNA that codes for a protein and its regulatory proteins

Question 2

define locus

Answer 2

• Location of gene on chromosome

Question 3

define allele

Answer 3

• Different forms (versions) of a gene

Question 4

define polymorphism

Answer 4

• Multiple forms (alleles) of a gene in population (>1% of pop)

Question 5

define homozygote vs heterozygote

Answer 5

• Possess the same alleles at a locus
• Possess different alleles at a locus

Question 6

define recurrence risk

Answer 6

• probability that the offspring of a couple will express the genetic disease. For single gene disorders, it does not depend on the number of previously affected/unaffected offspring. Depends on mode of inheritance of a disease

Question 7

define consultand

Answer 7

• the person who approaches a physician or geneticist for a consulation
  
  • this person may or may not be affected

Question 8

define proband

Answer 8

• The affected individual in the family who gains the attention of the physician due to a genetic condition

Question 9

describe autosomal dominant disorders

Answer 9

• precense of one mutant allele is sufficient to cause disease phenotype
• Heterozygous unless stated otherwise
• Skipped generations NOT common (vertical inheritance)
• Males + females affected equally
• Male to male transmission is seen

Question 10

name the autosomal dominant disorders

Answer 10

• Myotonic dystrophy
• OI
• Familial hypercholesterolemia (LDL receptor deficiency)
• Acute intermittent porphyria
• Marfan syndrome
• Huntington’s disease
• Achondroplasia
• Neurofibromatosis type I

MO FAM HAN!!!

Question 11

describe myotonic dystrophy

Answer 11

• Mutation in the DMPK gene
• Most pleiotropic phenotype of all unstable triple repeat disorders
• Characterized by:
  
  • wasting of the muscles
  • cataracts
  • heart conduction defects
  • endocrine changes
  • myotonia (clenched muscles)

Question 12

describe achondroplasia

Answer 12

• FGFR3 mutations
• FGFR3 codes for a transmembrane receptor that is involved in differentiation of cartilage to bone
  
  • Overactive FGFR3 –> severely shortened bones (GAIN OF FUNCTION)
• Mutations in FGFR3 result in severe stunting of growth

Question 13

describe neurofibromatosis (NF1)

Answer 13

• Mutations in the NF-1 gene that codes for neurofibromin protein
• NF-1 is caused by different mutations in the NF-1 gene (allelic heterogeneity)
• NF-1 gene codes for neurofibromin which is a tumor suppressor protein

Question 14

symtoms of neurofibromatosis

Answer 14

• cafe-au-lait spots
• neurofibromas: swellings on the skin
• Lisch nodules in the iris of the eye
• NF1 is a classic example of a disorder that exhibits variable expressivity but has high penetrance

Question 15

define haplo-insufficiency

Answer 15

• loss-of-function mutations in which half normal levels of the gene product result in phenotypic effects. Reduced protein levels are not sufficient to carry out the normal functions
  
  • ex: cell membrane receptors (FH)
  • acute intermittent porphyria (enzyme deficiency, heme can’t be produced fast enough)
  • OI

Question 16

describe dominant-negative mutations

Answer 16

• a mutant gene product interferes with the function of the normal gene product
  
  • Ex: collagenopathies such as OI type II, III or IV; also Marfan Syndrome (defect in fibrillin)

Question 17

describe gain-of-function mutations

Answer 17

• result from increased levels of gene expression or the development of a new function of the gene product
  
  • Ex: Huntington disease and achondroplasia

Question 18

define autosomal recessive

Answer 18

• Autosomal recessive disorders are expressed in the homozygous state
• Generally, both parents are carrier of the disease causing mutant allele
• Autosomal recessive disorder are usually seen in only one generation of a pedigree (horizontal inheritance)
• Males and females are affected in almost equal freq.

Question 19

describe the role of consanguinity in autosomal recessive pedigree

Answer 19

• In Western culture, consanguinity is usually NOT the cause of an AR disorder in a family
• However, the more rare a disorder is, the more likely consanguinity plays a role

Question 20

name the AR disorders

Answer 20

• Alpha1-antitrypsin deficiency
  
  • A1AT protects lungs from elastase –> disease causes COPD and other lung problems
• SCID due to adenosine deamine deficiency
  
  • ribonucleotide reductase causes reduction in dNTPs, which compromises immune system
• Sickle cell anemia
• Congenital deafness
• Hemochromatosis (delayed age of onset)
  
  • Overload of iron –> dysfunction of other organs
• Alkaptonuria (delayed age of onset)
  
  • can’t process Phenylalanine and Tyrosine. Makes urine black.
• Phenylketonuria
  
  • causes build up of phenylalanine to toxic levels
• Homocystinuria
  
  • results in excess homocysteine
• Cystic Fibrosis
• Galactosemia
  
  • Metabolism of galactose diminished, leads to toxic levels of galactose 1 phosphate –> englarged liver, kidney failure, brain damage
• Tay-Sachs disease (HEXA deficiency)

Question 21

describe loss-of-function mutations

Answer 21

• molecular basis for AR disorders
• result in either reduced activity (hypomorph) or complete loss of gene product (null allele or amorph)
  
  • examples include enzyme deficiencies
• The carrier usually does not have phenotypic manifestations
• A heterozygous carrier has 50% of the normal level of enzyme activity

Question 22

AR SCIDS due to ADA deficiency

Answer 22

• Purine degradation pathway
• If ADA (adenosine deaminase) is deficient, the build up of dATP is toxic to B-cell and T-cell development

Question 23

describe pseudo-autosomal dominant

Answer 23

• An autosomal recessive condition present in individuals in 2 or more generations of a family, thereby appearing to follow a dominant inheritance pattern
• An affected parent may have an affected child
  
  • appears vertical transmission
• Explanations
  
  • High carrier freq. of the disorder
    
    • sickle cell anemia in Africa
  • Higher incidence of consanguinity
    
    • Geographical, social or religious isolation

Question 24

name the 4 factors that increase the incidence of an AR trait in a population

Answer 24

1. consanguinity
2. heterozygote advantage
3. Genetic isolation
   
   1. Geographic, such as outports in Newfoundland
   2. Religious, such as Amish, Hutterites, etc
   3. Cultrual (language) such as Asian pop in UK
4. Assortive mating
   
   1. People associate and marry with “like”
      
      1. hearing or visually impaired individuals or couples with PKU

Question 25

describe the X and Y sex chromosome

Answer 25

* 950 genes on the X ch * Males are said to be hemizygous * 148 genes on the Y ch * mostly related to spermatogenesis

Question 26

describe X-linked recessive disorder inheritance

Answer 26

* When father affected, all daughters are carriers * When mother affected, all sons are affected * **Skipped generations common** * **Male to male transmission is not seen**

Question 27

name the X-linked RD

Answer 27

* Glucose 6-phosphate dehydrogenase deficiency (G6PD) * Hemophilia A and B * Red-green color blindness * X-linked SCID * Lesch-Nyhan syndrome (HGPRT deficiency) * Dystrophin associated muscular dystrophy * Duchenne (sever) * Becker (milder) ***_G_***IVES ***_H_***ER ***_R_***UGRATS ***_X_***-***_L_***INKED ***_D_***ISORDERS

Question 28

describe DMD

Answer 28

* DMD tends to be lethal before the age of 30--this means that there is a very ***_low reproductive genetic fitness_*** * **Pseudo**hypertrophy of the calf * muscle fibers of the gastrocnemius muscle are replaced with adipose cells, which makes it look muscular