Transcript Down Syndrome: A Complex Disease

Down Syndrome: A Complex
Disease
Dr Una Fairbrother
Down Syndrome (DS)
Affects one in about 700-1000
newborns
Most significant genetic cause of
mild to moderate mental retardation
Due to alterations in neural
development.
Trisomy 21 or DS
Only autosomal aneuploidy not
lethal in the fetal or early postnatal
period
DS phenotypes show variable
penetrance, affecting many
different organs
Clinical features of neonates
with DS
Flat facial profile,
90%
Hypotonia, 80%
Poor moro reflex,
85%
Hyperflexibility of
joints, 80%
Excess skin on
back of neck,
80%
Slanted palpebral
fissures, 80%
Pelvic dysplasia, 70%
Anomalous ears, 60%
Dysplasia of mid joint
of 5th finger, 60%
Simian crease, 45%
Down Syndrome – Disease
Phenotype
Mental retardation,
Congenital malformations of the heart
and gastrointestinal tract,
Duodenal stenosis or atresia,
Imperforate anus,
Hirschsprung disease,
Leukemia,
Hearing loss,
Alzheimer disease
and others
Human Chromosome 21
Many other disorders involving
Chr21 genes
165 hits on OMIM including:
Familial amyotrophic lateral
sclerosis (SOD1 gene)
Bethlem myopathy (COL6A1, A2
and A3)
Acute myeloid leukemia (AML1)
Chromosome 21 Structure
Length of the short arm can vary
greatly between individuals
First example of large genomic
region that can expand or contract
on a scale of many mega bases
Long arm: 225 genes originally
identified (545 on chromosome 22)
How Does Trisomy Arise?
95% of DS arises from non-disjunction
of homologous chromosomes during 1st
meiotic division in oogenesis
Homogeneity means that phenotype
severity cannot be predicted from the
karyotype
Need to understand the pathology and
identify candidate genes
Down Syndrome Research
Functions of most of the
Chromosome 21 genes are largely
unknown
As is their contribution, to the DS
phenotype.
Trisomy and Disease
How does an extra copy of all or part of
Chr21 result in the DS phenotype?
Specific case of the more general
problem - how does chromosomal
imbalance produce abnormalities in
morphology and function?
No single mechanism explains the
consequences
No simple solution to counteract its
phenotypic impact.
Trisomy and Disease:
Theories
Amplified developmental instability
hypothesis:
DS phenotype due to non-specific
disturbance of chr balance
Or… Gene dosage hypothesis:
DS due to cumulative effect of
overexpression of specific chr 21 gene
products
Corroborated experimentally in mouse
models
Some genes undergo dosage
compensation
Stage and tissue specific
Or Interaction effects
Through interaction of Chr21 genes
products with:
each other
the whole genome
transcriptome
Proteome
Possibly through trans acting effects
A proposed unifying model for the genetic
mechanisms acting in autosomal trisomy
Fitzpatrick (2005) TIGS 21:249-253
Mouse Models
useful to elucidate contribution of
specific genes to the DS phenotype.
Strategies:
assess single-gene by overexpressing
single or combinations of genes
assess effects of overexpressing large
foreign DNA pieces, (YACs or BACs) in
transgenic mice
mouse trisomies that carry all (usually
lethal) or part of MuChr16, which has
regions of conserved homology with
HuChr21.
Down Syndrome Critical
Regions (DSCRs)
Loci in the DS critical regions (DSCRs)
may have major effect
Approach limited by high phenotypic
variation among DS individuals
To date little evidence of association
between any particular phenotypic trait
and overexpression of a specific Chr21
gene.
Postgenomics
Even knowing the molecular defect, it is
difficult to decipher the complex
pathophysiology of the disease,
Developmental consequences of the
trisomy
Impact on behaviour and cognitive
function.
Facing a new era postgenomics where the goal is to
identify protein function and
physiological role of gene products.
Congenital Heart Defects and
DS
40% of trisomy 21 individuals have
CHDs
incidence in the euploid
population, 0.8%
Frequency of types of CHD in
Down Syndrome
Congenital Heart Defect (CHD)
Atrioventricular septal defect (AVSD)
Defect in fusion of endocardial cushions
Ventricular septal defect (VSD)
Failure of interventricular septum to close
Atrial spetal defect
Incomplete fusion of endocardial
cushions
Tetralogy of Fallot, 4 defects including
VSD
Patient ductus arteriosus, closure usually
occurs shortly after birth.
Other
Frequency
43%
32% (accounts for 35% of
normal individuals)
10%
6%
4%
5%
CHD Schematic
Endocardial cushion
Atrium
Ventricle
Heart
septa
ASD
AVSD
VSD
Trisomy 21 and CHD
If CHD phenotype is caused by
overexpression of a gene/s on
chromosome 21 then
why do not all individuals with
DS have a CHD?
May be related to specific alleles
and their protein products, which
function well in the diploid but not in
the trisomic state.
Fig.1: “Critical regions” of
chromosome 21
CHD
Critical
Regions
on
Chr21
Represen
-tative
markers
tested in
our
families to
date:
S=D21S
Genes in order
cen gene tel
(telomeric to
marker at left)
Key genes and
markers in
region (>2000
total known)
"DOWN
SYNDROM
E
CRITICAL
REGION"
TRISOM
Y IN
Ts65Dn
MOUSE
(PARTIA
L
TRISOM
Y 16)
"CHD
CRITICA
L
REGION"
(Korenbe
rg et al.)
REGION
OF
HETERO
TRISOM
Y IN
TRISOMI
C
CHILDRE
N WITH
VSD
Chromosom
e 21
cytogenetic
band limits
Non-llinear
scale: each Bar
is approx 5Mb
kbp
approx
from
pter
(not to scale)
21p
centromere
S1951
S215
S258
STCH,NRIP1
S16,S120
S13,s46
S1/S11
S1905
S8
NCAM2
S111
GABPA
APP
S82
GAPDP, BACH1
GRIK1
S300
S226
SOD1,CTBP2,
IFNAR2
D21S58
IFNAR
GART, SON3
CRYZL1
S235
ATP5O,DSCR1
S65
RUNX1
S17
S167
KCNE1, TPRD
DCRA,DYRK1A
DCRB
S259
KIR4.2
S338
S55
ERG
ETS2
S3
S343
C21LRP(DSCR2
)
HMG14
WRB
S168
SH3BGR
PCP4
S23,S349
DSCAM
S53
S64
MX2
S1260,S356
MX1
S19,S359
S42
S49,S360,S18
69
HOXGT
PKNOX1,
S361
CBS, CRYAA
Cystatin B,
S1979
HES1
PFKL
S400
C21orf2
S1870, S154
S171
COL6A1
COL6A2
S1575
UBE2G2
SMT3A,
CD18
COL18A1
D21S112
12743
21q11.1
12825
21q11.2
21q21.1
21q21.2
21q21.3
21q22.13
21q22.2
21q22.3
13536
13657
17990
19648
24101
24246
27663
28014
30024
31594
31689
31954
32881
33081
34018
35153
35783
36418
36660
36745
37169
37464
37539
37671
37741
37813
38228
39207
39498
39722
40810
41261
41386
41436
42478
42644
42673
42917
43113
43150
43230
43800
44342
44467
44920
How Might haplotypic diversity
Cause CHD in DS?
Variants interact indirectly/ directly with
other loci modulating phenotypes
Functionality of gene drops below critical
levels, endocardial cushions fail to fuse
Hypothesis: combinations of mutations
embedded in particular haplotypes, in
trisomic individuals, disturb the
supramolecular structure of a vital
protein and modulate the predisposition
of an individual to a single or several
types of CHD.
Do all CHD arise from the same
mechanism?
4 CHDs in individuals+ DS, related but
do not occur at same time in gestation
Counter-intuitive that a single, simple
mechanism is responsible for all CHDs
Variants may interact indirectly/directly
with other loci to modulate varying
phenotypes
(compound?) heterozygosity for rare,
functionally deficient alleles, may cause
analogous CHD in non-syndromic,
euploid individuals.
Heterotrisomy, a significant
contributing factor to ventricular
septal defect associated with
Down syndrome?
 Baptista MJ, Fairbrother UL, Howard CM, Farrer MJ, Davies GE, Trikka
D, Maratou K, Redington A, Greve G, Njolstad PR, Kessling AM. Hum
Genet. 2000 107:476-82.
Heterotrisomy for a gene or genes in a
narrowed region region is a contributing
factor to the pathogenesis of VSD in trisomy
21
Either through the presence of three different
specific alleles or through the presence of
specific combinations of alleles.
Down syndrome congenital heart
disease: a narrowed region and a
candidate gene.
 Barlow GM, Chen XN, Shi ZY, Lyons GE, Kurnit DM, Celle L,
Spinner NB, Zackai E, Pettenati MJ, Van Riper AJ, Vekemans MJ,
Mjaatvedt CH, Korenberg JR.Genet Med. 2001 3:91-101.
These data suggest that the presence of three
copies of gene(s) from the region is sufficient
for the production of subsets of DS-CHD.
Propose DSCAM as a candidate for VSD.
Encodes a cell adhesion molecule, spans
more than 840 kb of the candidate region, and
is expressed in the heart during cardiac
development.
DSCR1 gene expression is dependent on
NFATc1 during cardiac valve formation and
colocalizes with anomalous organ development
in trisomy 16 mice.
 Lange AW, Molkentin JD, Yutzey KE Dev Biol. 2004
15;266(2):346-60.
Nuclear factor of activated T cells or DSCR1
regulatory protein in calcineurin/NFAT signal
transduction pathway.
expressed during valvuloseptal developmentin the endocardium of the developing
atrioventricular and semilunar valves, the
muscular interventricular septum, and the
ventricular myocardium.
Candidate for abnormal development of heart
in DS
Cell type-specific over-expression of
chromosome 21 genes in fibroblasts and fetal
hearts with trisomy 21.
 Li CM, Guo M, Salas M, Schupf N, Silverman W, Zigman WB, Husain S,
Warburton D, Thaker H, Tycko B BMC Med Genet. 2006 15;7:24.
Expression microarrays
Expression differed across cell/tissue types.
MX1 up in senescent +21 fibroblasts. (MX1 is an
interferon target)
Interferon signaling a candidate pathway for
senescence
GART up in fetal hearts with +21
Abnormal purine metabolism may have a role in
cardiac defects.
Complex disease
 non-mendelian- familial aggregation, but no clear
segregation.
 suggests causative agents and physiological
mechanisms; evolution, development, homeostatic
processes.
 generally more frequent than single-gene disorders.
 single-gene disorders and complex diseases have
multiple genetic, developmental, and environmental
factors. In single-gene disorders, one gene has a
pronounced effect in producing the phenotype.
 Complex diseases is the major contributor to
morbidity/mortality in developed countries.
 Single-gene disorders are a smaller burden of disease
and death than do complex diseases.