Name two reasons, why some mutations have a dominant effect?
Haploinsufficiency
dominant-negative mutation
Why do some mutations have a dominant effect?
XXX occurs, when
a diploid organism has only a single copy of a gene (other copy inactivated by mutation)
single functional copy does not produce enough of a gene product to bring up a wild type condition
causing an abnormal or diseased state
A mutation that leads to a mutant protein that disrupts the activity of the wildtype proetin in the multimer is a XXX
Criteria of autosomal inheritance
both genders are equally affected
children of an affected parent have a likelihood of 50 % inheriting the condition
transmissioin from father to son
penetrance = likelihood that an individual with the pathogenic variant will show symptoms
variable expressivity = same mutation, but different phenotype
sporadic cases caused by de novo pathogenic variants or germinal mosaicism
phenotype of heterozygotes can resemble this of homozygotes
germinal mosaicism
= spontaneous defect in sperm/egg
—> low risk for second child haviung the same mutation, but ore-natal diagnostics possible
Types of short stature
1) normal stature
2) proportionate short stature
3) disproportionate short stature
3a) rhizomelic
3b) mesomelic
diseases of short stature
achondroplasia (rhizomelic)
hypochondroplasia (disproportionate, but milder than achondroplasia; 130-150 cm)
Thanatophoric dysplasia type 1 and 2
Achondroplasia - features
disproportionate/rhizomelic (< 120 cm)
increased head size
splayed fingers (can’t align them)
reduced mobillity in elbows
progressive narrowing of the spinal canal initial muscular hypotonia -> delay in motor development
typical radiological features
Müller: „Komplexe Fehlbildungen“ in
Hübler Jorch : Neonatologie , 2. Auflage Thieme Verlag 2019
1) stenosis of spinal canal lower spine
2) square pevis and horizontal acetabulum
3) club-shaped and transparent proximal femur
4) upslanted distal metaphyses of femur
Thanatophoric dysplasia type 1 and 2 - comparison
Type 1
Type 2
Type 2 w clover leaf skull deformity
narrow thorax -> lethal
as type 1
micromelia
bowed bones
straight bones
FGFR3 (Fibroblast Growth Factor Receptor; 4p16)
Mutations of Hypochondroplasia mostly located…
Mutations of Achondroplasia mostly located…
Mutations of Thanatophore Dysplasia mostly located…
FGFR3 structure
by: doi: 10.3390/cells8060614
Craniosynostosis - name of sutures
coronal suture (front)
sagittal suture (top)
lamboid suture (back)
Craniosynostosis - diseases
Muenke syndrome (isolated coronal synostosis)
Crouzon syndrome
Pfeiffer syndrome
Apert syndrome
uni- or bilateral coronal synostosis
short & broad medial phalanges of fingers & toes
fusion of carpal and tarsal bones
coronal synostosis
high forehead
hypoplastic midface
exophthalamus (“Glotzauge”)
beaked nose
broad distal phalanges
type 1: clasic
type 2: clover leaf skull, ankylosis in the elbows
type 3: severe proptosis, ankylosis in the elbows
coronal synostosis, often combined with sagittal + lamboid synostosis
premature closure of all sutures (except lambdoid)
turribrachycaphulus
small pointed nose
flat midface
developmental delay
down slanted palpebral fissures
syndactyly of 2-5 fingers and toes
Craniosynostosis - gene & causative mutation
gene: FGFR1/2/3
mutations -> gain of function -> cartilage => bone
(Pro -> Arg-mutation in Ig2-Ig3-joint)
FGFR1 = Pfeiffer syndrome
FGFR2 = Apert syndrome
FGFR3 = Muenke syndrome
name of genotype associated with inactive FGFR3
CATSHL =
CAmptodactyly
Tall Stature
Hearuing Loss
possible drugs for FGFR related diseases (chondroplasia)
inhibiting FGFR3 ligands
Problem of old fathers (selfish sperm mutations)
Huntington disease (characteristics)
autosomal dominant
manifestation at 35-45 years
movement disorder
personality changes
dementia
Huntington disease - cause
trinucleotide-repeat-expansion (CAG = Glutamin)
normal: n < 35
HD: n > 39
Huntingtin gene
Huntington disease - anticipation
= if father = affected (~100 % likelihood)
earlier manifestation/more severe symptoms in subsequent generations
when & which symptoms -> not able to forecast
symptoms can change from generation to generation
Myotonic dystrophy - symptoms
progressive myopia
distal progressive msucle weakness
Weakness of facial muscles
further systems:
heart (myrrhythmias)
brain (developmental delay, dementia)
testes (atrophy)
eye (cataract)
diabetes mellitus
Myotonic dysrtophy - anticipation if
Myotonic dystrophy - clinical phenotypes
average population: 4-30 repeats; chr. 11
Unstable Triplet Disorders (Huntingtin gene)
type 1 = repeat within coding-region = toxic protein
HD (other example: SCA)
type 2 = non-coding region (3’ UTR) = toxic RNA
MD: RNA forms hairpin structure in nucleus -> can recruit RNAse (CLC1, ISNR, TNNT2/3) from other RNAs/proteins
Last changeda year ago
