Shit

In South Africa

Can be traced bacck to one couple

port vine coloured urin (porphyrins in the urin) and sensitivity to sun -> skin blistering

autosomal dominant

confirmed when male to male transmission

a single gene that gives rise to apparently unreleated effects

McKusick

Watson & Crick

Rosalind Franklin

maurice wilkins

37

Single-gene abnormalities

Chromosomal disorders

polygenic (multifactorial) disorders

some individuals get more affected or different

(e.g. polycystic kidney disease)

due to enviromental factors or modifying effects of other genes

Monosomy, Trisomy, Tetrasomy

Tripleudy, Tetraploidy

Reciprocal

Robertosoniam

Pericentric

Paracentric

genocopies

phenocopy

two different mutations at the same locus

often people affected with recessive disorder have it except parents are related

Y-linked

daltonism, hairy ears

women for X-linked recessive but the mutant X is the active in most cells

X-linked dominant disorder

heterozygous females can have a mosaic pattern of abnormal pigmentation

Usually lethal for male embryos

e.g. PCDH19

heterozygous state is harmful

or X-inactivision is disturbed

short-stature homebox

in the pseudoautosomal region on the X

can be transmitted via cross-over to the Y

mutation causes the Leri-Wil dyschondrosteosis

gout

presenile baldness

hormone dependent

1 : 20 000

25-30% maternal uniparental disomy of chromosome 15

in 50-60% 2mb interstitial deletion

in 15% submicroscopic deletion

almost always on paternal chromosome

genes affected: SNRPN, or the genes for it’s expression (ICR, MKRN3, SNURF,snRNA …)

short stature, obesity, learning difficulty, hypogonadism

1 : 15 000

paternal uniparental disomy or imprinting of the maternal chromosome

epilepsy, severe learning difficulties, ataxic gait and happy affect (happy puppy)

loss of only one gene: UBE3A

via mutation in UBE3A ligase gene or ICR

damage to nerve cells via ubiquitin

all mitochondria are identical

-> no disease or severe

gap genes

pair-rule genes

segment polarity genes

HOX genes then are responsible for what is expressed

split-hand-foot malformation

aka ectrodactyly

key gene is DLX5 or enhancer which is found in DYNC1I1

shows reduced or non-penetrance (not known why)

fibroblast growth factors (FGFs) -> maintainance

BMPs (bone morphogenetic proteins) -> patterning in the mesoderm

get activated by ligand binding to their receptor

extracellular signaling polypeptides

33 members of cytokines

BMPs - acting through SMAD proteins

induced in cell cycle, cell migration, cell size, gastrulation, axis specification

for axial deviation of presomitic mesoderm

precise temporally defined wave of cycling genes

dependent on cross-talk of Notch, Wnt and FGF pathways

Sonic hedgehog gene

induces cell proliferation

expressed in the notochord, brain and zone of polarizing activity of developing limbs (more -> more fingers)

it’s receptor is the PTCH

receptor for SHH

inhibits the transmembrane protein Smo but when SHH binds the inhibition is off

activision of Smo leads to activation via GLI

when mutated -> Gorlin syndrome

inhibited by PTCH

induces signaling cascade with GLI

caused by mutation or deletion in SHH

incomplete cleavage of developing brain

most severe presents in cyclopia

regulate expression of other transcription factors, cell adhesion proteins, cell movement, cell death

4 Hox gene clusters in humans with 39 genes overall

contain 180 bp

one HOX gene can compensate for the other

HOXB10 is more similar to HOXC10 than to HOXB11

caused by mutation in HOXA13

autosomal dominant

shortening of the 1st and 5th digits

hypospadias and bicornuate uterus

mutation in HOXD13

autosomal dominant

insertion of additional digit

more severe in homozygotes

triplet-repeat expansion

130 aminoacid transcription regulator domain

9 PAX genes

5 of those associated with developmental abnormalities

PAX3 gene mutation

autosomal dominant

hearing loss, depigmentation of hair, skin or iris

PAX3 can also cause cancer (alveolar rhabdomyosarcoma)

mutation in MITF or SOX10

mutation in PAX2

causes renal malformation and structural defects in parts of the eye (optic nerve, retina, …)

Mutation in PAX6

absense of the iris

key feature of the WADR syndrome -> gene deltetion including PAX6 on chromosome 11

These genes act aas transcription factors

bind to DNA via the “finger-like” loop projection of 4 amino acids that form a complex with a zinc ion

e.g. GLI3

large deletion or translocation involving GLI3

head, hand, foot abnormalities (polydactyly & syndactyly)

caused by frameshift mutations in GLI3

polydactyly, hypothalmic hamartomata and imperforate anus

holoprosencephaly

lateralis defect

situs inversus

(situs solitus is normal)

encodes for cell surface tyrosine-kinase

gain-of-function mutation is present in thyroid cancer

loss-of-function in Hirschsprung disease

can also cause cancer (MEN2A, MEN28, medullary thyroid carcinoma)

fibroblast growth factor receptors

for embryogenisis, cell division, migration and differentiation

has three extracellular immunoglobin like domains

two intracellular tyrosine kinase domains

mutation in FGFR2

-> needed for fusion of the 2nd and 3rd immunoglobin-like domain

premature fusion of cranial sutures, hand-foot abnormalities

mutation in FGFR3 -> replacement of glyine by arginine

most common genetic short stature

enlarged head and short proximal limbs

autosomal recessive

mutation in DYNC2H1

46 chromosomes due to fertilazation of an empty ovum by dispermy or one and endoreplication

all paternal

can undergo malignant change into invasive choriocarcinoma

-> treated with chemotherapy

69 chromosomes (triploidy)

23 maternal 46 paternal due to dispermy or endoreplication

almost no surviving rate of fetus

but only in rare cases malignant

referred as lyonization

15-16 days after gestation (5000 cells)

achieved by methylation initiated by the XIST gene

In sex organs both X-genes are active

is responsible for inactivision of X-chromosome via methylation via RNA

does not inactivate the Pseudoautosomal region

visible in women with X-linked ocular albinism or incontentia pigmenti

mutant chromosome is active

from 6 weeks develops into female unless there is th etestis-determining factor from SRY gene (single exon)

triggers inhibition of a receptor for SOX9

mutation of androgen receptor gene on X-chromosome

partial (PAIS)

and complete (CAIS) develope breasts and female external genitalia but no internal

adrenal hyperplasia -> excess of androgen

testicular structures are present

tetrameric

F: 2𝛼2𝛾 <1%

A: 2𝛼2β - 97%

A2: 2𝛼2𝛿 - 2-3%

𝛿 differs from β by 10 amino acids

𝛾 by 39

Gower 1

Gower 2

Portland 1

same amino acid sequence but different nucleotides

on chromosome 16

β is on 11

sequende of 6-20 kb 5’ to 𝜀 controls switching of β-like globin genes

similar for 𝛼

point mutation

deletion

frameshift

insertion

chain termination

fusion chain (unequal crossing over)

on β chain point mutation

glutamic acid to valine

-> sickle cell disease

on 𝛼 chain

chain termination leading to adding of 31 residues by a point mutation in stop codon

𝛿 and β chain fuse unequally together during meiosis because of sequence similarities

more genes -> anti-lepore

less genes -> lepore

hemoglobin variant that is more stable in it’s reduced form

less oxygen affinity

structural globin variants HbS

autosomal recessive inheritance

distorts shape of RBC under deoxygenated condition

-> less oxygen supply

Treatment consists of prophylactic penicillin (preventing sepsis) and use of hydroxyurea -> increase of level of HbF

20% HbF is needed

heterozygous have small increased risk of sudden death

homozygous get sickle cell crisis …….

risk of pulmonary hypertension and heart failure

disorder of synthesis of globin chains

Philadelphia gene is translocated from gene 22 to 9

-> transfer of the Abelson (ABL) oncogene

-> fusion with BCR protein

translocation of the c-MYC oncogene

to chromosome 14 on to a heavy chain immunoglobin locus -> overexpression

N-MYC in 30% of neuroblastoma cases

MYC, N-MYC, L-MYC in lung carcinoma

in 20% of breast cancers ERBB2, MYC and cyclin D1 are amplificated

important for RAS-MPK signaling pathway (cell division, …)

associated with neurofibromatosis type 1 and Noonan/cardio-facio-cutaneous/Costello group of syndromes

follows autosomal inheritance but is recessive because it needs loss of one allele to occur

Loss of heterozygosity (LOH) due to recombination, conversion, deletion or point mutation

RB1 acting as a tumor suppressor gene

-> also associated with malignancies later in life (osteosarcoma, firbrosarcoma, …)

encodes for p105-Rb

p105-Rb forms a complex with E2F which regulates the proceding of cell cycle into S phase when p105-Rb is phosphorylated (inactivated)

no/or hyperphosphorylated RB1 -> cancer

tumor suppressor gene

most frequently mutated of all known cancer genes

encodes for p53 which cooperates with activated Ras

hereditary mutation of Tp53

autosomal dominant

causes adrenal carcinomas, sacromas and breast cancers

Loss of imprinting of the IGF2/H19 locus causes many tumors (e.g. Wilms tumor)

maternal or paternal allel is no longer silenced

IGF: insuline-like growth factor

hypermethylation can lead to inactivation of tumor suppressor genes

CpG islands which are normally not methylated will, when methylated, change the chromosome structure -> silencing of genes

Ataxia telangiectasia

and other chromosome breakage disorders

(autosomal recessive)

1 in 40 people

order of gene defects:

APC -> K-ras -> DCC, SMD4, SMD2 -> TP53

-> Metastasis

mutation causes Familial adenomatous polyposis

causes Multiple endocrine neoplasia type 2

breast-ovarian cancer

breast caner

Neofribromatosis 1

mutation in APC

autosomal dominant

developing multiple polyps of the large bowel which can carcinomatous change -> in 90% with FAP bowel cancer developes

onset of colonic cancer in mid forties

autosomal dominant

inactivision of MSH2 caused by deletion in TACSTD1 (transcription exceeds into MSH2) (40%)

mismatch repair in MLH1 account for 50% of cases

instead of LOH it shows presence of new alleles called microsatallite instability (MSI)

present in 15% of colorectal cancers

high levels of MSI suggest a lynch syndrome related mutation

LOH: HER2, c-MYC and Ras, and cyclin D1 & E

amplification: EMSY (interacts with BRCA2)

tumor suppressors: RB, TP53, PTEN

susceptibility genes. BRCA1 and BRCA2

If Her2, estrogen receptors and progesteron receptors are all negative the tumor is not supported by hormones but are more agressive

If hormone supported it’s Tamoxifen or Herceptin

If triple negative it’s PARP inhibitors

early onset familial cancers

for 40-50% of all familial breast cancer and carriers have 20-60% risk for ovarian cancer

for 30-40% of familial breast cancer

Males with BRCA2 mutation have 6% for breast cancer

10% are due to single gene mutation (BRCA1, BRCA2, Lynch syndrome

Muteted gene is ATM

short telomeres

chromosome breakage syndrome

autosomal recessive

Isoniazid

-> acetylation

metabolism of drugs via adding an acetyl group into the molecule

done by action of N-Acetyltransferase

mostly in the liver

elimination of morphine and codeine

by action of G6PD

sulfonamide

and

diet

enzyme in red blood cells

eliminates the treatment for malaria drug:

Primaquine

X-linked recessive

10% of afro-caribbean males affected

absense of embryo

missense mutation of PTPN11 (accounts for half of NS cases)

often gain-of-function

spina bifida or anencephaly

defective closure during first month of embryonic life

can happen with trisomy 13 and 18 (5-10%) as well as the rare autosomal recessive Meckel-Gruber syndrome

risk can be resuced by periconceptional multivitamin supplementation

when PDGFRA and PAX1 mutation in combi it’s 100%

Chorionic villi sampling 11-12 week

Amniocentesis 16 weeks

prenatal screeniong tests (triple and quatruple from mothers serum at 16 weeks)

example of mosaicism diploidy/triploidy

skin skows Blaschko lines

learnig difficulties

puffy extremities or neck webbing, short stature and ovarian failure

short stature due to SHOX gene on pseudoautosomal region

Estrogen replacement therapy

high fore head, large ears, long face, prominent jaw

learning difficulties, autistic features

female carriers can show facial features

locus is called FRAXA

-> CGG trinucleotide repeata

Other genes identified: FRAXE, FRAXF & FXTAS

normal person has 1-50 CGG repeats

51-58 intermediate

59-200 premutation -> unstable

>200 full mutation

normal and premutation via PCR

full mutations via southern blotting

due to deletion of 22q11

autosomal dominant

Autosomal recessive

deficiency of phenylalanine hydroxylase that converts phenylalanine into tyrosine

mutation in the PAH gene

phenylalanine is converted into phenylpyruvic acid and excreted

affeted individuals hav eblonde hair and blue eyes

treatment only with diet

children born to mothers with phenylketuria have a learing disability

deficiency of homogentisic acid oxidase

-> homogentisic acid accumulates and is excreted via urine -> dark urine when exposed to air

autosomal recessive

mutation of HGD

dark ear wax or joints

autosomal recessive

deficiency of tyrosinase

tyrosinase-negative (OCA type 1) and tyrosinase-positive (OCA type 2)

uncontrolled eye movements and lack of pigment

OCA type 1has mutation in tyrosinase gene

OCA type 2 in P-gene

deficiency of the enzyme galactose 1-phosphate uridyl transferase which is needed for metabolism of galactose (dietary sugar)

newborns present vomiting, jaundice, lethargy, failure to thrive

untreated can lead to mental retardation

treatment includes feeding them with a milk substitute without lactose or galactose

deficiency of glucose 6-phosphatase

-> needed for breakdown of liver glycogen to release glucose

newborns have enlarged liver and fast heart rate due to hypoglycemia

treatment by frequent feeding

deficiency of lysosomal enzyme ⍺-1,4-glucosidase

-> needed for breakdown of glycogen

newborn develope an enlarged heart in the first or second year cause by accumulation of glycogen in cardiac muscle

most common disease for ambiguous genitalia in female

90% have 21-Hydroxylase deficiency

25% have salt-losing form

less common:

-Desmolase deficiency -> pseudohermaphroditism

-5⍺-reductase daficiency -> under-masculinization

treated with cortisol and, when salt-losing form, with fludrocortisone

autosomal dominant

most common in AD in Western europe

individuals are at higher risk for premature coronary artery diesease

present in childhood with Xanthomata (deposition of lipid)

Low cholesterol uptake caused by abnormal synthesis/transport/binding of Low-density-lipid receptors

Is followed by dietary restrictions

another treatment is with statins -> less cholesterol production

not enough lysosomal enzymes for break down of macromolecules

when born children are normal but with more time there is an accumulatino of macromolecules

Mucopolysaccharidoses:

Hurler Syndrome (MPS 1)

Hunter Syndrome (MPS 2)

defective degradation of carbohydrate side chain of acid mucopolysaccharide -> accumulation of sulfated polysaccharides -> features of CNS, skeleton, vascular system etc.

6 different types which are all autosomal recessive, except Hunter which is X-linkes

treated with enzyme replacement

or bone marrow transplantation

most severe MPS

hearing loss, curve of lower spine, poor growth, enlarged liver and spleen

urinary excretion of dermatan and heparan sulfate

X-linked MPS

also excretion of dermatan and heparan

deficiency of the enzyme iduronate 2-sulfatase

-> needed fordegradation of glucosaminoglycans

inability to breakdown sphingolipids

inability of sphingolipid degradation

deposition of lipid and glycolipid in brain, liver and spleen

leads to progressive mental deterioration with seizures leading to death in childhood

16 types (Tay-Sachs and Gauchers disease)

autosomal recessive

more common in Ashkenazi Jews

present by 6 months with poor feeding and floppiness

later with developmental regression and deteriorates, deafness, visual impairment

death occurs at age of 3

presence of the cherry-red spot in macula

reduced hexosaminidase A due to deficiency of the subunit β-hexosaminidase -> leads to accumulation of sphingolipid GM2 ganglioside

disorder of copper metabolism

X-linked recessive

presents with vomitting, seizures etc

characteristic is th lack of pigment in hair

serum copper and ceruloplasmin is low

gene codes for a copper transport protein

treating with exogenous copper

copper metabolism disorder

autosomal recessive

presents in childhood over involuntary movements, abnormal tone, changes in behavior

Kayser-Fleischer rings around iris

abnormal liver function and also high levels of ccopper in liver

gene codes for copper ATPase from hepatocytes into bilary system

treated with D-penicilin

symptoms are neurological signs: ataxia, dystonia, dementia, encephalopathy, seizures

and myopathic: weakness, cardiomyopathy, hypotonia

others are deafness, diabetes,

MERRF and MELAS

point mutation in lysine tRNA

mutation in gene for leucine tRNA

autosomal dominant with almost full penetrance

trinucleotide repeat of CAG

gene affected is HTT

up to 26 is normal

to 35 is mutable

39 is redeuced penetrance

40 and more is full disease with late onset …

juvenile is often at least 55 repeats

symtoms are chorea, memory impairment

in juvenile instead of chorea its ridgity

40 different gene loci

1:3000

mostly autosomal dominant

type 1 is demyelinating and PMP22 (and in some cases MPZ)

is also more severe and earlier onset

type 2 is axonal MFN2 and NEFL

inverted champange bottle

type 4 is AR

CMTX1 is X linked dominant(5-10%)

on the SMN1 gene (always, mostly by deletion of exons 7-8) and SMN2 (the rest is point mutation)

autosomal recessive

carrier incidence is 1:50

type 1 most severe and earliest onset with 6 months

treatment ist spinraza and gene therapy

carrier determination is difficult because 4% of the population have two copies of SMN1

average onset with 56

SOD1 accounts for 20% of cases

expasion of GGGGCC hexanucleotide repeat

autosomal dominant with 100% penetrance

50% are due to de novo mutation

neurofibromin-1 is the gene -> tumor suppressor

Ras activity is up as fuck

large deletions are more affected

neurofibromin 2

deletion and point mutations

with deletions being milder than point mutations

most common

1:3500 males

pseudohypertrophy of calves

x-linked recessive

mutation of dystrophin gene

2/3 deletions and others are duplications which affect the reading frame

often happens during paternal meiosis

dystrophin links intracellular actin with extracellular laminin in muscles

levels less than 3% are diagnostic

CK are increased

DMPK

CTG trinucleotide repeat

expasion of CCTG into first intron of ZNF9

-> its protein binds RNA

AR

almost all males are infertile

mutation of CFTR to be precise of the subunit p.Phe508del

treatment with OKAMBI but only for p.Phe508del