Chapter 12. Molecular Diseases and Inborn

Error of Metabolism

Gene

mRNA

Protein

Transcription

Translation

Gene mutationMutant gene

No RNAAbnormal mRNA

No proteinAbnormal protein

Other proteins

Enzymes

Molecular diseases

Inborn error of metabolism

Outline

1. Molecular diseases– hemoglobinopathy– receptor protein disease

2. Inborn error of metabolism– phenylketouria, PKU

Molecular DiseaseMolecular Disease

In 1949, Linus Pauling and his collaborators In 1949, Linus Pauling and his collaborators published a study in the journal Science entitled published a study in the journal Science entitled "Sickle Cell Anemia, a Molecular Disease." "Sickle Cell Anemia, a Molecular Disease."

A disease in which the manifestations are due to A disease in which the manifestations are due to alterations in molecular structure and function alterations in molecular structure and function

ＳＡ

WHY HEMOGLOBIN?WHY HEMOGLOBIN?

AAvailability vailability AAbundance bundance EEase of purification ase of purification CColor olor EEssential physiological function ssential physiological function DDisease related isease related KKnown structure nown structure

Human HemoglobinsHuman Hemoglobins

Two types of globin chainsTwo types of globin chains–– 2 2 chains (141 amino acids)chains (141 amino acids)

–– 2 2 chains (146 amino acids)chains (146 amino acids)Hb GowerHb GowerⅠⅠ 2222

Hb Gower Hb Gower ⅡⅡ 2222

Hb Portland Hb Portland 2222

Hb F Hb F 2222Hb AHb A22 2222Hb A Hb A 2222

Globin Genes-like genes 16p13.3 30kb

-like genes 11p15.5 70kb

5’ 3’ 16p

-like genes12kb 3.7kb

5’ 3’1 31 32 99 100 141

5’ 3’1 30 31 104 105 146

5’ 3’ 11p G A

-like genes13.4kb

13.8kb 5.7kb3.4kb

Development of erythropoiesis in the human fetus and infant. Types of cells responsible for hemoglobin synthesis, organ(s) involved, and types of globin chain synthesized at successive stages are shown.

Organization of the human globin genes and hemoglobins produced in each stage of human development.

5’ 3’ 16p

5’ 3’ 11p G A

-like genes

-like genes

Hemoglobins

22

Hb GowerⅠ

22

Hb GowerⅡ

22

Hb Portland

22

Hb F Hb A2

22 22

Hb A

Developmental period Embryonic Fetal Adult

Abnormal hemoglobinsAbnormal hemoglobins–– Structurally abnormal hemoglobin chains Structurally abnormal hemoglobin chains

ThalassemiasThalassemias–– Abnormal production of normal chainsAbnormal production of normal chains

HemoglobinopathiesHemoglobinopathies

Hemoglobin Structural VariantsHemoglobin Structural Variants

Point mutationPoint mutation–– Missense mutationMissense mutation–– Nonsense mutationNonsense mutation–– Stop codon mutationStop codon mutation

Frame shift mutationFrame shift mutation Insertion or deletion of codonsInsertion or deletion of codons Fusion geneFusion gene

Sickle Cell Hemoglobin

Hemoglobin variants due to:Hemoglobin variants due to:–– single base pair substitutionsingle base pair substitution

Sickle cell anemia（Hb S）

Hemoglobin Variants: Chain

Hemoglobin Variants: Chain

Hemoglobin variants due to:Hemoglobin variants due to:–– Stop codon muatationStop codon muatation

e.g. Hb Constant Spring

chain: codon 142 TAA--CAA

CGU UAA GCU GGA GCC UCG …..UAA141 173

Hemoglobin variants due to:Hemoglobin variants due to:–– Framshift mutationFramshift mutation

Hemoglobin variants due to:Hemoglobin variants due to:–– Codon insertion or deletionCodon insertion or deletion

e.g. Hb Grady : 116 117 118 119 117 118 119 120 … 141

e.g. Hb Gun Hill : 90 96 97 98

Hemoglobin variants due to:Hemoglobin variants due to:Fusion gene G A

unequal cross-overG A

G

A

G A

Fusion gene

G A Hb Lepore

Hb anti-Lepore

Thalassemias

thalassemia - decreased chains

thalassemia - decreased chains

Barts hydrops fetalis Barts hydrops fetalis (fetal or early neonatal death)

Alpha ThalassemiaAlpha Thalassemia

••----//--

••//

••-- //

••--//--

••----//

• ----//----

NormalNormal

Silent carrierSilent carrier

MinorMinor

Hb H disease Hb H disease (mild to severe anemia)

Hb H

A2 F A H

PH8.6 - +

H A F A2

PH6.5 + -

Heinz小体

Hb Bart’s hydrops fetalis

Beta Thalassemia Decreased chain production + - decreased synthesis o - absent synthesis Homozygous condition provides a wide range of

disease and heterozygous condition can range from mild to moderately severe

thalassemiaHbA↓， HbＦ↑， Hb A2 ↑

按临床症状分类：• 重型贫血：严重的进行性溶血性贫血，（纯合子） 发育障碍，肝脾肿大，地中海

特征性面容。• 轻型贫血：轻度贫血，黄疸，脾大，

低色素• 中间型：为变异型的纯合子或双重杂合子，

介于重型和轻型之间。

根据肽链受抑制情况分类o地贫：完全不能合成链+地贫：能合成部分链（约5～30%)o地贫：、合成同时受抑制 o

+

Receptor protein disease

Familial hypercholesterolemia,FH

常染色体显性遗传AD, 杂合子

患者过早出现角膜弓、冠心病。纯合子患者可在儿童期发生冠心病，5-30岁出现心绞痛和心肌梗塞,甚至猝死。

LDL receptor: 19p13.1-13.2，45kb，18 exons.

Mutation: deletion, insertion and point mutation.

Inborn error of metabolism

An inherited enzyme deficiency leading to the disruption of normal bodily metabolism

Accumulation of a toxic substrate(compound acted upon by an enzyme in a chemical reaction)

Impaired formation of a product normally produced by the deficient enzyme

ES3S4 S4

S1S2 S2S3 S3S4

ES1S2S1 S2ES2S3 S3

Gene

Enzyme&

Metabolic pathway

mRNA

S5 S6

ES3S4 S4

S1S2 S2S3 S3S4

ES1S2S1 S2ES2S3 S3

Gene

Enzyme&

Metabolic pathway

mRNA

Phenylalanine-tyrosine Metabolic Pathway