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
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•
•
•
•
•
•
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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