Molecular Disease
Medical Genetics
1902,Garrod AE
the incidence of alkaptonuria:
a study in clinical individuality
1948,Horlein H & Weber G
1949,Pauling L
Sickle cell anemia,a molecular disease,
Science,110,543-548,1949,
Molecular Disease
A disease in which the manifestations
are due to alterations in protein structure
and quantity.
Structure of Hemoglobin
1?2?1
5? 3?
16pter-p13.3
1 31 32 99 100 141
Hemoglobin Alpha Chain
11p15.5
ε G? A? ψ?1 δ β
5? 3?
Hemoglobin Beta Chain
1 30 31 104 105 146
0 2 4 6 8 Birth 2 4 6 8
Months
100
80
60
40
20Per
cen
tag
e o
f
gl
ob
in
sy
nt
hes
is(
%)
Development of Hemoglobin
δ
δ ε
α
γ β
α
Developmental
Stage Hemoglobin
Hemoglobin
Composition
Embryo Hb Gower1?2?2
Hb Gower2?2?2
Hb Portland?2G?2?2A?2
Fetus Hb F?2G?2?2A?2
Adult Hb A?2?2
Hb A2?2?2
Development of Hemoglobin
Hemoglobinopathy
Abnormal hemoglobin is production of
an abnormal globin chain.
Thalassemia is reduced production of
selected globin chains.
Hereditary disorders that can result
in moderate to severe anemia.
Terminology of Hemoglobin
Hemoglobins & abnormal hemoglobins
discovered earlier have been given letter
designations
Hb A; Hb F; Hb S
More recently discovered hemoglobins
have been named by the city or location
of discovery
Hb Constant Spring; Hb Harbin
Amino Acid Substitution
Greek letter designates affected globin chain
Amino acid substitutions are denoted by the
three letter abbreviation for the normally
occurring amino acid followed by an arrow
followed by the three letter abbreviation for the
substituted amino acid
Superscript number designates affected amino
acid(s)
Pathogenesis
Missense mutation
Sickle cell disease (HbS)
Missense Mutation
Normal
Sickle Cell Disease
Sickle Cell Anemia
Sickle Cell Trait
Mix
Sickle Cell Disease
Sickle Cell Disease
CH NH2
CH 2
CH 2
COOH
COOH
C NH2
C
CH 3
COOH
CH3H
H
Sickle Cell Disease
Sickle cell anemia (HbS),code 5~7
MstⅡ,CCTNAGG?A,CCTGAGGAG
S,CCTGTGGAG
Sickle Cell Disease
Sickle Cell Disease
Benin － － － － ＋ ＋ －－
CAR － ＋ － － － ＋ ＋＋
Senegal － ＋ － ＋ ＋ ＋ ＋＋
Asian ＋ ＋ － ＋ ＋ ＋ ＋－
MstⅡ,CCTNAGG
ε G? A? ψ?1 δ β
5? 3?
Sickle Cell Disease
Sickle Cell Disease
Sickle Cell Disease
O2
HbA
HbS
Sickle Cell Disease
Sickle Cell Disease
Sickle Cell Disease
Sickle Cell Disease
Missense Mutation
Hb Harbin
Alpha chain —— AAG 16 ATG
16Lys→Met
Terminator codon mutation
Pathogenesis
Missense mutation
Hb Constant Spring
Alpha chain —— TAA 142 CAA (Gln)
Terminator Codon Mutation
Nonsense mutation
Terminator codon mutation
Pathogenesis
Missense mutation
Nonsense Mutation
Hb McKees-Rock
Beta chain —— TAT (Tyr) 145 TAA
Frame shift mutation
Nonsense mutation
Terminator codon mutation
Pathogenesis
Missense mutation
Frame Shift Mutation
Hb Wayne
Alpha chain —— TCC (138),C loss
Codon insertion or deletion
Frame shift mutation
Nonsense mutation
Terminator codon mutation
Pathogenesis
Missense mutation
Codon Insertion or Deletion
Hb Grady
Alpha chain —— Phe-Thr-Pro insertion (116)
Fusion gene
Codon insertion or deletion
Frame shift mutation
Nonsense mutation
Terminator codon mutation
Pathogenesis
Missense mutation
Fusion Gene
Hb Lepore
Difference of beta & delta chain
VHLTPEEKSA
VHLTPEEKTA
VTALWGKVNV
VNALWGKVNV
DEVGGEALGR
DAVGGEALGR
LLVVYPWTQR
LLVVYPWTQR
FFESFGDLST
FFESFGDLSS
PDAVMGNPKV
PDAVMGNPKV
KAHGKKVLGA
KAHGKKVLGA
FSDGLAHLDN
FSDGLAHLDN
LKGTFATLSE
LKGTFSQLSE
LHCDKLHVDP
LHCDKLHVDP
ENFRLLGNVL
ENFRLLGNVL
VCVLAHHFGK
VCVLARNFGK
EFTPPVQAAY
EFTPQMQAAY
QKVVAGVANA
QKVVAGVANA
LAHKYH
LAHKYH
Fusion Gene
ATGGTGCATC TGACTCCTGA GGAGAAGACT GCTGTCAATG CCCTGTGGGG CAAAGTGAAC
ATGGTGCATC TGACTCCTGA GGAGAAGTCT GCCGTTACTG CCCTGTGGGG CAAGGTGAAC
GTGGATGCAG TTGGTGGTGA GGCCCTGGGC AGATTACTGG TGGTCTACCC TTGGACCCAG
GTGGATGAAG TTGGTGGTGA GGCCCTGGGC AGGCTGCTGG TGGTCTACCC TTGGACCCAG
AGGTTCTTTG AGTCCTTTGG GGATCTGTCC TCTCCTGATG CTGTTATGGG CAACCCTAAG
AGGTTCTTTG AGTCCTTTGG GGATCTGTCC ACTCCTGATG CTGTTATGGG CAACCCTAAG
GTGAAGGCTC ATGGCAAGAA GGTGCTAGGT GCCTTTAGTG ATGGCCTGGC TCACCTGGAC
GTGAAGGCTC ATGGCAAGAA AGTGCTCGGT GCCTTTAGTG ATGGCCTGGC TCACCTGGAC
AACCTCAAGG GCACTTTTTC TCAGCTGAGT GAGCTGCACT GTGACAAGCT GCACGTGGAT
AACCTCAAGG GCACCTTTGC CACACTGAGT GAGCTGCACT GTGACAAGCT GCACGTGGAT
CCTGAGAACT TCAGGCTCTT GGGCAATGTG CTGGTGTGTG TGCTGGCCCG CAACTTTGGC
CCTGAGAACT TCAGGCTCCT GGGCAACGTG CTGGTCTGTG TGCTGGCCCA TCACTTTGGC
AAGGAATTCA CCCCACAAAT GCAGGCTGCC TATCAGAAGG TGGTGGCTGG TGTGGCTAAT
AAAGAATTCA CCCCACCAGT GCAGGCTGCC TATCAGAAAG TGGTGGCTGG TGTGGCTAAT
GCCCTGGCTC ACAAGTACCA TTGA
GCCCTGGCCC ACAAGTATCA CTAA
δ β
δ β
δ β
G? A15? 3?
Fusion Gene
Hb Lepore
Difference of beta & delta chain

Lepore
Anti Lepore
Fusion Gene
Hb Lepore
Difference of beta & delta chain
Thalassemia
Thalassemia is inherited anemia caused
by decreased synthetic rate of hemoglobin.
Greek letter designates affected globin chain
－,Indicates a gene deletion
/,Indicates division between genes inherited from
both parents
+,Indicates diminished,but some production of
globin chain by gene
0,Indicates no production of globin chain by gene
Terminology of Thalassemia
Alpha Thalassemia
Alpha thalassemia occurs when one or
more of the four alpha chain genes fails to
function.
With alpha thalassemia,the,failed”
genes are almost invariably lost due to a
genetic accident.
Alpha Thalassemia
Types Genotype Deletion Alpha protein
Hemoglobin Barts?0/?0 －－ /－－ 0
HbH disease?+/?0?－ /－－ 25%
Mild anemia?A/?0/－－ 50%
+/?+?－ /?－
Silent Carrier?A/?+/?－ 75%
Normal?A/?A/ 100%
1?2?1
5? 3?4.2 Kb
+ thalassemia
Leftward deletion,The loss of?2,Asian
Rightward deletion,The loss of?2(3?) and?1(5?)
Pathogenesis
3.7Kb
1?2?1
5? 3?
0 thalassemia
The loss of?,,1,?2,and 5? end of?1
The loss of,1,?2,and?1,Southeast Asia
The loss of1,?2 and?1,Mediterranean sea
The loss of?2 and 5? end of?1,Greeks
Pathogenesis
These occur less commonly than the
deletion types.
Pathogenesis
Nondeletion forms of alpha thalassemia
Beta Thalassemia
Beta thalassemia occurs when one
or two of beta chain genes fails to
function.
With beta thalassemia,the beta
globin gene is present,but suppressed
and produces little beta globin
protein.
Nonfunctional mRNAs
Splice junction mutants
Pathogenesis
Promoter mutants
mRNA capping or tailing mutants
Pathogenesis
Nonfunctional mRNAs
Splice junction mutants
Deletion forms of beta thalassemia
Pathogenesis
Missense mutation
Nonsense mutation & Termination codon
mutation
Frame shift mutation
Fusion gene
Point mutation in the uncoding region
Pathogenesis of Hemoglobinopathy
Most hemoglobin variants are caused by
point mutations
Deletion