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Autosomal monogenic inheritance
Dr. habil. Kohidai Laszlo
Department of Genetics,
Cell- and Immunobiology
Semmelweis University
Budapest
/2014/
Autosomal - Dominant
Minimum one of the parents is affected
Phenotype of homozygotes is more severe than heterozygotes
Male and female are affected equally
Male and female transmit evenly
Affected x Non affected results 50%<affetced (sick) phenotype
Vertical pedigree
Frequency of the mutations shows correlation to the age of father
AD mutations influence receptor, structural or carrier proteins
Variable expressivity and penetrance
Dominant autosomal
~ 2200 known dominant trait
frequency 0.1-3/1000/birth
most frequently affected organs:
skeleton
central nerve system
4p16.3
Achondroplasia
Frequency 1:25000
FGFR3 gene mutation
(fibroblast-growth
factor receptor 3)
Longitudinal growth of tubular bones is
affected
Limbs are affected
forehead is dominant, middle part of the
face is less developed
Achondroplasia
Rhinoceros unicornis
Teleoceras fossiger
sheeps
FGFR3 gene
locus: 4p16.3
DNA: 16.5 Kb; 19 exon; exon 1 is not known in human
RNA: 4.0 Kb mRNS; alternative splicing
exons 7 and 8: two mRNA isoforms IIIb and IIIc
Expressed in: brain, cartilage, liver, kidney, inner ear
The protein
806 aa; 115 kDa
function: tyrosin kinase receptor
structure:
extracellular part 3 Ig-like loops (I, II, III)
strongly hydrophobe TM domain (22 aa) -TM
intracellular domain with ttyrosine kinase activity -TK
Mutationsa of the FGFR3 gene
3 diseases are associated to the
mutations of FGFR3
Arachnodactylia – Marfan syndrome
Antoine Bernard-Jean Marfan
(1896)
Gabrielle
Arachnodactylia – Marfan syndrome
Tutankhamen pharaoh
Ehnaton
pharaoh
Mary of Scotland
Abraham Lincoln
Marfan syndrome – Symptomes
affected bones and joints
height
chest
long fingers
hyperflexibility
Marfan szindróma - Symptomes
Eye and vision
myopia (short sight)
axis of the eye is longer
position of the lens is abnormál
Heart and circulation
valve prolapse
aorta aneurysm
hypotension
Frequency of mutations is
increasing by age
Marfan syndrome
Fibrillin gene (FBN1)
15q21.1
There are several mutations of
fibrillin gene (see green bands)
Fibrillin protein
~ 60 domain
binds 47 Ca2+
similar to epidermal growth
factor (EGF)
Osteogenesis imperfecta I.
blue sclera
Penetrance 100%
extremely fragile bones
Deafness or loss of hearing
(penetrance is less than 100%)
Level of pleiotropy is high
Osteogenesis imperfecta
COL1A1 gene
17q21.31-q22
COL1A1 -
18 kb
52 exon ( 6 – 49: alpha helical domain)
short exons: 45 bp, 54 bp or repeats
of these two
RNA: 2 RNA: 5.8 kb and 4.8 kb difference in 3’ UTR
Protein : 140 kDa
Structure of collagen fibre
Healthy
Osteogenesis
imp. Type I.
Central helical domain:
- 338 x repeat of Gly-X-Y triplet
- X and Y amino acids are
frequently prolins (Pro)
Osteogenesis Imperfecta: Mutation map of collagen
Osteogenesis imperfecta
Familiar hypercholesterinaemy
Main clinical symptoms:
- early onset of cardial and
circulatory system diseases
(myocardial innfarction,
vascular diseases of brain and
peripherial blood vessels)
- xanthoma
- diseases of the eye
Familiar
hypercholesterinaemy (FH)
LDL lifespan in the body
healthy: 2.5 days
FH: 4.5 days
LDL-level in sera is increased
Reasons:
- Mutation of
LDL-receptor
- ApoB defect
LDL
19p13.1-13.3
Familiar hypercholesterinaemia
Mutations of LDL-receptor
Heterozygtes:
1:500-1000
Homozygotes:
1:1.000.000
Most frequent mutation:
9. exon 408 kodon CTG → CTA
Val → Met
Familiar hypercholesterinaemy
Outcomes of LDL-receptor mutation
Ligand kötő domain
EGFP domain
O-linked
szénh.dom.
Citopl.
domain
Membrán
Joseph Goldstein, Michael Brown
(Nobel Prize 1985)
Trinucleotide-repeat diseases
Huntington chorea
Starts in age 35-44
Complex disease of locomotor,
cognitive and psychiatric
symptomes
CAG trinucleotide repeats
Number of CAG repeats:
Normal - >26
Transient 27-35
Low penetrance 36-39
High penetrance above 40
Huntington chorea
Huntington chorea - (CAGn)
4
Gain-of-function
mutation
The function of
the Huntingtin gene
in human is not
known
Huntington chorea
Huntington chorea – CNS parts affected
Huntington chorea
Effects of huntingtin on gene level
Inhibited expression of Dopamine D2 receptor gene
Huntington chorea
Effects on cytoskeleton level
BDNF - brain-derived neurotrophic factor
Transport of vesicles containing neurotransmitters
via microtubular system:
Huntingtin – huntingtin-related-protein (HAP) – dynactin - dynein
Correlation between the ‘CAG’ repeat-number
and the age of onset
George Huntington (1850-1916)
Grandfather and father were
farmer doctors – their anamnestic
files supported Huntington to
describe the disease
The disease was described in 1872
Medical and Surgical Reporter of
Philadelphia
chorea = maniac dance
Trinucleotide-repeat
CAG
Anticipation – Trinucleotide
repeat
The disease is expressed in
gradually more severe levels
and earlyier in the offspring
generations
Sickle cell anemia
Co-dominant
Haemoglobinopathy
HBB gene – 11 chrs.
b-globin chain mutation
HbS variant
Haemoglobin structural change
HbA
HbS
Due to the irregular
structure of HbS:
The membrane of RBC is
damaged
The affected RBCs are
eliminated in great
numbers in the
peripheral organs, (e.g.
kidney/spleen)
The O2 transport is
disturbed
Malaria – spreading cycle
Plasmodium falciparum
Plasmodium vivax
Selective advantage of heterozygotes:
Sickle cell anemia
Malaria
Selective advantage of heterozygotes:
Sickle cell anaemia
Malaria
BUT:
The ratio is decreasing
by changing the environment
E.g. Cyprus – frequency of thalasszemia
is decreasing
Autosomal
Recessive
Parents of the affected person
usually not expressing the trait, they
are heterozygotes (Aa)
Expression rate in male:female is 1:1
Transferred by male and females
Co-saguinity of parents is frequent
Risk to have an affected individual in
the offspring is 25% (Aa x Aa)
Horizontal pedigree
Recessive autosomal
1700 known human recessive traits
More than 15% is enzymopathy
(e.g. phenylalanine hydroxylase, hexose aminidase)
Mutations of haemoglobin
Multiplex allelism – several mutations of one gene are
responsible for the development of a
symptome
Complex heterozygote – an individual who possess two
diverse, mutant allels of a gene
mutáns allélját hordozza
E.g. Cystic fibrosis – 850 different mutations
Frequency of recessive diseases
There is a significant difference in diverse ethnic groups
REASON: reproductive advantage of
heterozygotes to homozygotes
ENVIRONMENTAL FACTORS
Selective advantages of heterozygotes
Other reasons: directed marriages in some ethnic groups
b-Thalassemia
(thalassa = sea)
b-Thalassemia
(thalassa = sea)
haemoglobin b chain mutations
short life span of RBCs
O2 transporter capacity is decreased
Cystic fibrosis
Cystic fibrosis
chief symptome is the obliteration of
tubular organs
affected organs: lung, pamcreas,
gonads
laboratory: sweat Cl- ion conc. increased
deafness
Selective advantage:
Cholera – results high loss of Cl- ions
Aa heterozygotes
(aa – CF sick, AA – cholera infected,
Aa CF–infected BUT no loss of Cl-ions)
Cystic fibrosis
deletion of F508 (Phe)
deletion hits an ABC transporter
role in Cl- ion release from the cell
Cystic fibrosis
chloride-channel
mutation
1/25 frequency
850 mutation
Development
of
clinical
symptoms
in cystic fibrosis
Tay-Sachs disease
GM2 gangliosid metabolism affected
HAXA gene
b-hexose aminidase enzyme is
affected
(lysosomes in neurones)
CNS diseases:
- paralysis
- demency
- blindness
- early death
GM2 gangliosid
deposites in the brain (LM and TEM)
Tay-Sachs disease
Lysosome
membrane phospholipid
GM2
GM2 activator
GM3
GM2
Hex A
Tay-Sachs disease
phosphorylation of Man is failed on HA-a subunit
enzym is not transported into lysosomes
Tay-Sachs disease
Carrier frequency: 1:300
Askenazi Jewish population:
1:30
15q23-q24
Environmental effect:
Galicia – bad hygenic conditions
- high mortality due to TBC – AA homozygotes
- high mortality due to Tay-Sachs – aa homozygotes
Aa heterozygotes have reproductive advantage
Sandhoff disease
Both hexose aminidase A and B are
affected
GM2 ganglioside storage – toxic
effects
infantile, juvenile and adult forms
mental ret., muscular probl., eye,
organiomegaly
Saskatchewan, Christian Maronits
(non Ashkenazi Jewish origin)
5q12-q13
Other monogenic
recessive
autosomal
diseases
Other recessive autosomal
diseases
12
Phenylketonuria – deficient
phenylalanin hydroxylase
11, 15, 9, X
Albinism
- mental retardation
- slow development
- Tyr -> melanin synthesis is
failed
- Enzyme def.: failed tyrosinase
enzyme
- affected organs skin and eye
- more known forms
Galaktosemia
Albino and normal kangaroos
Albino Barking Deer
Albino crab
Albino dingo
Effect of ethnic
diferences on the
expression of
inherited diseases
Factors complicating determination
of inheritance
•
•
•
•
•
•
•
•
New mutations
Germ line mosaicism
Late onset
Decreased penetrance
Variable expressivity
Pleiotropy and heterogeny
Genomic imprinting
Anticipation
Expressivity
- level of expression of the
inherited trait
(severity of disease)
Penetrancy – level of transmission of the trait
from generation to generation
Pleiotropy
gene
Phenylalanin-hydroxylase gene
mutation
Symptome < Syndrome
Trait 1
Trait2
Pleiotropy: Stickler syndrome
Collagen 2A1 mutation
Symptomes:
- Retina-ablation
- Myopy
- Cleft lip
- Cleft palate
- Size of mandibula
is small
- Problems with joints
Heterogeny
Forms:
Gene 1
Gene 2
trait
Phenotype ~ (clinical) – mutations of one gene –div. phenotype
Allel ~ – allels of the same gene – phenotype is similar
Locus ~ – genes are different – phenotype is similar
Deafness
Forms:
Retinitis
pigmentosa
•Aut.Dom.
•Aut. Rec.
•X-linked
Hirshprung dis.
– Phenotype
- Allel
- Locus
Cystic
fibrosis
Genotype
Phenotype
Environment
~
Phenocopy
Retinoic acid-defic.
22q11 deletion
- Aorta def.
- Small ears
- IQ decr.
- Cleft palate