Biochemical Genetics:

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Biochemical Genetics Metabolic Disorders
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Garrod's Biochemical Genetic Hypothesis In the
early part of this century (1902, 1908, 1910),
Sir Archibald Garrod studied alkaptonuria and
proposed a biochemical genetic hypothesis that
the information for producing specific enzymes is
inherited. Some basics 1.Alkaptonuria is
characterized by the darkening of urine after its
been exposed to air for some time. It is easily
diagnosed in infants 2.Alkaptonuria occurs in
families, as an autosomal recessive
pattern Garrods Idea 1.If one enzymatic step
in a series of biochemical reactions was not
occuring, it would lead to an accumulation of an
intermediate in the reaction sequence. 2. The
accumulating intermediate might be excreted in
the urine instead of the usual end product of the
series of reactions.
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http//www.people.virginia.edu/rjh9u
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http//www.ncbi.nlm.nih.gov/disease/Phenylketo.htm
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Phenylalanine Phenotypes and Inheritance (http//w
ww.people.virginia.edu/rjh9u/pkuphen.html)
IQ Level No. of PAH molecules
PAH activity
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PAH Phenylalanine Hydroxylase
Structure of the phenylalanine hydroxylase
full-length model.
Source Erlandsen H and Stevens RC, The
Structural Basis of Phenylketonuria. Mol Genet
Metab. 1999 Oct 68(2)103-125.
http//data.mch.mcgill.ca/models/full.html
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The domains comprising each subunit of the
phenylalanine hydroxylase full-length model.
Source Erlandsen H and Stevens RC, The
Structural Basis of Phenylketonuria. Mol Genet
Metab. 1999 Oct 68(2)103-125.
http//data.mch.mcgill.ca/models/full_dom.html
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The main chain ribbon is coloured light green.
PKU/PAH mutations have the carbon atoms in
orange and residues which interact with the
mutant site residues and iron ligands are in dark
green.
A view of seven of the residues lining the active
site that cause PKU/PAH.
Source Nature Structural Biology 4, 995
(1997). http//data.mch.mcgill.ca/models/act_site_
seven.html
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Close-up of the PKU R252 mutation, including the
hydrogen bonding.
Source Erlandsen H and Stevens RC, The
Structural Basis of Phenylketonuria. Mol Genet
Metab. 1999 Oct 68(2)103-125.
http//data.mch.mcgill.ca/models/R252_mut.html
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Close-up of the PKU R408 mutation, including the
hydrogen bonding.
Source Erlandsen H and Stevens RC, The
Structural Basis of Phenylketonuria. Mol Genet
Metab. 1999 Oct 68(2)103-125.
http//data.mch.mcgill.ca/models/R408_mut.html
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Location of PKU/PAH on Chromosome 12 (12q22-q24.2)
http//www.ncbi.nlm.nih.gov/cgi-bin/Entrez/maps.cg
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Phenylketonuria Frequency Human
population Frequency of PKU Allele Frequency
Carrier Frequency Swedish
1/30,000 (0.000033) 0.0058
0.012 Irish, Scottish,
Yemenite Jews 1/5,000 (0.002)
0.014 0.028 US
Caucasian 1/10,000 (0.0001) 0.01
0.02 Chinese
1/16,000 (0.0000625) 0.0079
0.016 Japanese 1/119,000
(0.0000084) 0.0029
0.003 Turks 1/2,600
(0.0003846) 0.02
0.039 PKU Allele
Frequency square root of the frequency of PKU
individuals. Carrier
Frequency 2 x (1-PKU Allele Freq.)(PKU Allele
Freq.) or 2pq.
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Cystic fibrosis phenotype 1. In CF, the mucus
in the lungs is thicker and is not moved to the
mouth by the ciliated cells. It stays in the
bottom of the lungs which causes persistent
coughing and recurrent lung infections. 2.
In CF, the pancreatic gland that secretes
digestive enzymes becomes clogged. This causes
the formation of cysts and eventually the gland
becomes fibrous - thus the name cystic fibrosis
of the pancreas (as described by D. H. Anderson
in 1938). 3.Because the intestine does not
receive enough digestive enzymes, it results in
undernourishment and excess fats in the stool
(steatorrhea).
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Cont... 4.Reproductive ducts in most males
become blocked (sterility). 5. In CF, the
salt in sweat is not taken back up leaving a salt
residue on the skin and a salt deficit in the
body. 6.Autosomal recessive inheritance
established in 1946. 7.The CFTR gene was
located in 1989.
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Location of CFTR on Chromosome 7 (7q31.2)
http//www.ncbi.nlm.nih.gov/cgi-bin/Entrez/maps.cg
i
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http//www.people.virginia.edu/rjh9u/cfmap.html
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Cystic Fibrosis Allelic Variants for Cystic
Fibrosis Transmembrane Conductance Regulator
CFTR Mutations 990 Sequence variations 208
Cystic Fibrosis Genetic Analysis Consortium
Online Mendelian Inheritance in Man 0001 CYSTIC
FIBROSIS CFTR, PHE508DEL 0002 CYSTIC FIBROSIS
CFTR, ILE507DEL 0003 CYSTIC FIBROSIS CFTR,
GLN493TER 0004 CYSTIC FIBROSIS CFTR,
ASP110HIS 0124 PANCREATITIS,
IDIOPATHIC, SUSCEPTIBILITY TO CFTR, LEU997PHE
0125 CYSTIC FIBROSIS CFTR, 1-BP INS, 3622T
0126 CYSTIC FIBROSIS CFTR, NT3601, T-C, -20
0127 CYSTIC FIBROSIS CFTR, 1-BP DEL, 3876A
http//www.ncbi.nlm.nih.gov80/entrez/dispomim.cgi
?id602421
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Cystic Fibrosis Frequency U.S.
Population Frequency of CF Frequency of

Carriers
White 1/2,400
1/25 Hispanic 1/8,400
1/46 Black
1/14,000 1/60
Asian 1/89,000
1/150
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Heterozygous Advantage of CF mutations The
mutation that causes cystic fibrosis has survived
for about 50,000 years. Cystic fibrosis is now
the most common fatal genetic disorder among
Caucasians. Recent experiments on mice offer
evidence that suggests that the individuals who
are heterozygous for a CF mutation are protected
against diarrheal diseases (e.g. cholera)
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Cystic Fibrous Foundation http//www.cff.org/
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Familial hypercholesterolemia (FH) - A genetic
disease characterized by high levels of
cholesterol - Caused by defects in the
low-density lipoprotein receptor - It is an
autosomal dominant trait - About 1 in 500 people
are heterozygous for FH, making FH one of the
most common inborn errors of metabolism. -At
birth, FH-heterozygous people have a twofold
increase in cholesterol and they develop coronary
heart disease early 30s - Homozygotes number
about one in a million and have a severe form of
the disease in which coronary heart disease
begins during childhood and causes death by age
20.
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Location of LDL receptor on Chromosome 19
(19p13.3)
Chromosome 19
LDL receptor 19p13.3 Familial
Hypercholesterolemia
LDLR
http//www.ncbi.nlm.nih.gov/cgi-bin/Entrez/maps.cg
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LDL Receptor Gene
Indicated in blue at the bottom of the figure are
the effects of mutations on the function of the
molecule.
after Gelehrter, Collins, and Ginsburg
Principles of Medical Genetics 2nd Ed., 1998
(Williams Wilkins) http//www.people.virginia.e
du/rjh9u/ldlrecep.html