Grades

1
Grades

• Exam and quiz scores are posted,
• Roughly alphabetical, (WWU).
• Please check for accuracy,
• Extra Credit (not yet compiled),
• Seminars, Paper, odds and ends to be posted by
  Tuesday.

2
Email Extra Credit

• Your email extra credits (through 8 AM, June 7th)
  are posted. Ill count the entries as listed.
• If you placed more than one synopsis in an email,
  please put a star, or a mark by your name.
• Remember, you were instructed to send no more
  than one article per email.

Note some of you emailed the MCK paper. Thats
OK, I have both hard and soft copies.
3
Points

• Please dont panic over a few points,
• If you are close to a grade break, and have done
  a significant amount of extra credit, youll
  definitely get the benefit of the doubt.

4
Final

• Total point value is 100,
• Ill grade both sections on a 100 scale, and
  convert the totals to 100 pts.

5
Chapter Self Study Questions,

• Two ways to get a right answer,
• Best get it right.
• Just about as good (probably equal in points to a
  right answer),
• Explain why you cant answer the problem, suggest
  alternative approaches that youve considered, or
  make an assumption and answer it based on the
  assumption.

6
Due Tuesday, 4 PM(my office box BI315)

• Ill be in my office during the scheduled final
  hours,
• Tuesday, 1030 - 1230.

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Hereditary Fructose Intolerance

• Fructose intolerance was first noted in severely
  ill infants with recurrent hypoglycemia (low
  blood sugar) and vomiting, occurring at the time
  of weaning when fructose or sucrose is added to
  the diet and resulting in marked malnutrition.
• However, a 3-year-old brother of a severely
  affected infant was found to have hepatomegaly
  (enlarged liver), and hypoglycemic shock was
  precipitated by an oral test dose of fructose,
  although he was clinically healthy. He had a
  marked aversion to sweets and fruit.
• Subsequently, 2 adults, aged 33 and 39 years were
  identified with the same condition . In addition
  to the aversion to fructose-containing foods,
  remarkable absence of dental caries was noted.
• The defect resides in aldolase B, which catalyzes
  the cleavage of fructose-1-phosphate to form
  dihydroxyacetone phosphate and D-glyceraldehyde.

9
Phenotype

• Hypoglycemia,
• Depletion of ATP resources,
• Degradation of purine (G and A in DNA),
• Hypermagnesemia,

10
CLINICAL MANAGEMENT

• Limit, fructose and related sugarssucrose and
  sorbitol,
• Difficult, if not impossible in modern, Western
  society.

11
Glycolysis

• Cells are run by the energy produced through the
  oxidative conversion of glyceraldehyde
  3-phosphate to pyruvate and the coupled formation
  of ATP and NADH,
• Youve learned the conversion of glucose into
  G3P, but we cant live by glucose alone...

12
Liver, Kidney, Intestinal Mucosa

• In aldolase 'B'-deficient tissues, cytoplasmic
  accumulation of fructose-1-phosphate leads to
  sequestration of inorganic phosphate with
  resulting activation of AMP deaminase that
  catalyzes the irreversible deamination of AMP to
  IMP (inosine monophosphate), a precursor of uric
  acid.
• Depletion of tissue ATP occurs through massive
  degradation to uric acid and impairment of
  regeneration by oxidative phosphorylation in the
  mitochondria because of inorganic phosphate
  depletion.
• In the cell, ATP exists largely as a 11 complex
  with magnesium. Depletion of ATP in tissues leads
  to depletion also of magnesium concentration.

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Feeder Pathways for Glycolysis
14
Lactose intolerance

• Lactose Intolerance is divided into the following
  categories
• 1. Congenital Alactasia or hypolactasia This is
  an extremely rare condition except in
  Scandinavian countries. Babies with this
  condition do not gain weight and are dehydrated
  and extremely unwell.
• 2. Primary acquired or lactase non-persistence.
  This is an age related condition and usually
  occurs after weaning and before the age of six
  years. This affects approximately 70 of the
  worlds population and 10 of Australias
  population overall .
• 3. Secondary acquired or lactase non-persistence
  occurs as a result of damage to the small
  intestinal mucosa due to for example
  gastroenteritis, cows milk protein intolerance or
  coeliac disease.

OMIM 223000
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Polymorphic

• A149P and A174D frequencies near 1,
• no obvious advantage has been identified for
  heterozygotes, although physiological
  manifestestions of heterozygosity exist,
• Overall frequency in the population of
  homozygotes is between 1 in 15,000 to 1 in
  20,000.

16
Aldolase B Mutations

• gt 21 mutations that have been reported
• 15 of these are single-base substitutions,
• resulting in 9 amino acid replacements,
• 4 nonsense codons,
• and 2 putative splicing defects.
• The other 6 were deletions.
• Recurrent mutations were observed in exons 5 and
  9. Analysis suggests that the A149P and A174D
  mutations originated from a single founder and
  achieved a relatively high frequency through
  genetic drift.

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Mutant Alleles

• .0001 FRUCTOSE INTOLERANCE ALDOB, ALA149PRO
• A G-to-C transversion in exon 5 resulted in a
  substitution of proline for alanine at position
  149 of the protein within a region critical for
  substrate binding.
• .0002 FRUCTOSE INTOLERANCE ALDOB, ALA174ASP
• Point mutation found in Italy, Switzerland, and
  Yugoslavia but not in the UK, France, or the
  United States.
• .0003 FRUCTOSE INTOLERANCE ALDOB, LEU288DEL
• A 1-bp deletion in codon 288 causing a
  frameshift. The mutation seems restricted to
  Sicilian subjects.
• 0006 FRUCTOSE INTOLERANCE ALDOB, ASN334LYS
• In addition, in 11 unrelated Italian patients,
  researchers found a G-to-C transversion in exon 9
  which resulted in substitution of lysine for
  asparagine at position 334.
• .0008 FRUCTOSE INTOLERANCE ALDOB, ARG3TER
• A consanguineous family from eastern Turkey, has
  a C-to-T transition in codon 3 changing arg to
  stop codon.

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Structure/Mutation Sites

• Aldolase B associates in quartenary structure as
  a homotetramer,
• A149P and A147D mutations result in a reduced
  affinity between sub-units.
• Other mutation my retain quatenary structure, but
  lack enzymatic activity.

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OMIM
http//www.ncbi.nlm.nih.gov80/entrez/dispomim.cgi
?id229600
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Modern Disease
21
Slave Trade
22
Sickling and G6PD Defenciencies

• Heterozygotes carrying alleles for for red blood
  cell sickling disorders, and for and
  glucose-6-phosphate dehydrogenase deficiency are
  resistant to malaria.

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Sickle Cell Anemia

• Walter Clement Noel, a first-year dental student
  at the Chicago College of Dental Surgery, was
  admitted to the Presbyterian Hospital in late
  1904 where Ernest E. Irons, a 27-year-old intern,
  obtained a history and performed routine
  physical, blood, and urine examinations.
• He noticed that Noel's blood smear contained
  'many pear-shaped and elongated forms' and
  alerted his attending physician, James B.
  Herrick, to the unusual blood findings.

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Sickling Disease in Modern Culture

• Homozygotes for sickling disorders have from mild
  ranging to debilitating disorders,
• Heterozygotes and homozygotes have health
  complications in temperate climates due to cold
  temperatures, and endemic infections.

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G6PD Disease in Modern Culture

• First seen in WWII, African-American soldiers
  receiving an anti-malaria drug experienced
  haemolysis.
• Presently,
• Sulphanomides,
• Anti-pyretic drugs,
• Broad Beans.

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Questions?
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Functional Genomics(445)

• MWF (1-2 pm), Autumn Quarter,
• Literature driven course,
• Genomics,
• Sequencing.
• Reverse genetics,
• DNA Arrays, etc.
• Transcriptomics,
• DNA arrays,
• EST library analysis,
• etc.

• Proteomics,
• Protein Chips,
• 2-D gels,
• Mass Spectroscopy,
• Metabolomics,
• Phenomics,
• Who-knows-what-omics.
• Learn how to read and understand cutting edge
  papers,
• Low-key environment.

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"I guess there's cool stuff about science,"
Watanabe continued, "like space travel and bombs.
But that stuff is so hard, it's honestly not even
worth the effort."
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IMPORTANT INSTRUCTIONS FOR ADMINISTERING COURSE
EVALUATIONS PLEASE FOLLOW EXACTLY! 1.
INSTRUCTOR Tell students who will administer the
evaluation, and advise them whether they are
dismissed afterward. Then please read the
following two statements to the class exactly as
written, and LEAVE THE ROOM DURING THE EVALUATION
"I have scheduled time today for you to rate
the quality of this course. The University and I
take the evaluation of teaching very seriously
and hope you will approach this evaluation
thoughtfully. The results of this evaluation will
help to improve the course in the future, and
also may influence decisions concerning tenure,
promotion, or salary. Your participation is
voluntary and confidential to ensure
confidentiality, do not write your name on the
forms. There is a possibility your handwriting on
the written comment sheet might be recognizable
however, I will not see the results of this
evaluation until after the quarter is over and
you have received your grades." "Please be sure
to use a NO.2 PENCIL ONLY to fill in ovals on the
evaluation form."