Article

Increased frequency of the null allele at the complement C4b locus in autism

Department of Biology, Utah State University, Logan 84322-6800.
Clinical & Experimental Immunology (Impact Factor: 3.04). 04/1991; 83(3):438-40. DOI: 10.1111/j.1365-2249.1991.tb05657.x
Source: PubMed

ABSTRACT

Associations between C4 deficiency and autoimmune disorders have been found over the past several years. Since autism has several autoimmune features, the frequencies of null (no protein produced) alleles at the C4A and C4B loci were studied in 19 subjects with autism and their family members. The autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele (58% in both the autistic subjects and mothers, compared with 27% in control subjects). The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this increase was not significant. The fathers had normal frequencies of this null allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles.

Full-text

Available from: Dennis Odell
Clin.
exp.
Immunol.
(1991)
83,
438
440
Increased
frequency
of
the
null
allele
at
the
complement
C4b
locus
in
autism
R.
P.
WARREN,
V.
K.
SINGH,
P.
COLE,
J.
D.
ODELL,
C.
B.
PINGREE,
W.
L.
WARREN
&
E.
WHITE
The
Developmental
Center
for
Handicapped
Persons,
The
Department
of
Biology
and
the
Department
of
Psychology,
Utah
State
University,
Logan,
UT,
USA
(Acceptedfor
publication
5
October
1990)
SUMMARY
Associations
between
C4
deficiency
and
autoimmune
disorders
have
been
found
over
the
past
several
years.
Since
autism
has
several
autoimmune
features,
the
frequencies
of
null
(no
protein
produced)
alleles
at
the
C4A
and
C4B
loci
were
studied
in
19
subjects
with
autism
and
their
family
members.
The
autistic
subjects
and
their
mothers
had
significantly
increased
phenotypic
frequencies
of
the
C4B
null
allele
(58%
in
both
the
autistic
subjects
and
mothers,
compared
with
27%
in
control
subjects).
The
siblings
of
the
autistic
subjects
also
had
an
increased
frequency
of
the
C4B
null
allele,
but
this
increase
was
not
significant.
The
fathers
had
normal
frequencies
of
this
null
allele.
All
family
members
had
normal
frequencies
of
the
C4A
null
allele,
all
normal
C4A
and
C4B
alleles
and
all
BF
and
C2
alleles.
Keywords
autism
complement
C4B
null
alleles
INTRODUCTION
Autism
is
a
severe
developmental
disorder
characterized
by
abnormalities
in
the
manner
in
which
the
brain
collects
and
integrates
information
resulting
in
abnormal
communication
and
social
skills.
The
cause
of autism
remains
unknown.
However,
recent
investigations
suggest
that
this
disorder
shares
several
features
of
established
autoimmune
disorders,
including
genetic
susceptibility
(Folstein
&
Rutter,
1977;
Smalley,
Asar-
now
&
Spence,
1988),
helper
T
cell
alterations
(Stubbs
et
al.,
1977;
Warren
et
al.,
1986,
1990;
Yonk
et
al.,
1990)
and
other
immune
abnormalities
(Weizman
et
al.,
1982;
Todd
&
Ciare-
nello,
1985),
association
with
congenital
viral
infections
(Chess,
1977;
Stubbs,
1978);
and
a
four-to-five
times
greater
occurrence
in
boys
than
in
girls.
Recent
evidence
suggests
that
inherited
abnormalities
of
the
complement
C4
proteins
may
be
linked
to
certain
autoimmune
diseases
(reviewed
by
Kahl
&
Atkinson,
1988).
C4
is
composed
of
two
distinct
but
highly
homologous
glycoproteins,
C4A
and
C4B,
whose
structural
genes
are
found
within
the
MHC
on
chromosome
6.
C4A
and
C4B
genes
are
highly
polymorphic
with
each
having
a
null
(QO)
allele
which
is
functionally
silent
(no
protein
is
produced).
Homozygosity
for
the
null
allele
at
C4A
or
C4B,
which
is
quite
rare,
is
associated
with
slightly
reduced
C4
serum
levels.
Heterozygotes
have
a
null
allele
on
one
of
their
chromosomes
(at
either
C4A
or
C4B)
at
a
frequency
of
Correspondence:
Reed
P.
Warren,
Ph.D,
UMC
6895,
Utah
State
University,
Logan,
UT
84322-6800,
USA.
approximately
36%
and
30%,
respectively,
in
the
general
population
and
C4
protein
levels
which
are
usually
in
the
lower
end
of
the
normal
range
(reviewed
by
Kahl
&
Atkinson,
1988).
The
frequency
of
C4-deficiency
(null
alleles
at
the
C4A
locus)
is
increased
among
patients
with
SLE
(Fielder
et
al.,
1983;
Christiansen
et
al.,
1983),
insulin-dependent
diabetes
mellitus
(Raum,
Awdeh
&
Alper,
1981)
and
scleroderma
(Briggs
et
al.,
1986).
An
increased
frequency
of
null
alleles
at
the
C4B
locus
has
been
reported
in
patients
with
scleroderma
(Mollenhauer
et
al.,
1984)
and
schizophrenia
(Rudduck
et
al.,
1985).
Since
autism
displays
several
characteristics
of
autoimmunity,
we
have
performed
analysis
of
extended
haplotypes
in
autism.
SUBJECTS
AND
METHODS
Included
in
this
investigation
were
family
members
of
190
randomly
chosen
autistic
subjects
(17
male
and
two
female),
all
of
Northern
European
descent.
Each
family
included
one
autistic
child
and
both
parents.
In 14
of
these
families,
one
normal
sibling
without
the
symptoms
of
autism
was
also
available
to
be
studied.
The
diagnosis
of
autism
satisfied
DSM-
IIIR
criteria
for
infantile
autism
as
ascertained
by
at
least
two
psychiatrists
or
psychologists.
None
of
the
autistic
subjects
had
an
identifiable
cause
of
their
disease
and
all
were
living
at
home
at
the
time
of
study.
Also
in
the
investigation
were
62
randomly
chosen
normal
subjects
also
of
Northern
European
descent,
unrelated
to
the
autistic
subjects,
who
were
living
in
the
same
geographical
area
(Northern
Utah)
as
the
autistic
subjects.
Serum
samples
were
obtained
from
the
subjects
following
informed
consent
procedures.
The
genetic
typing
for
the
438
ADONIS
000991049100080Q
Page 1
C4B
null
alleles
in
autism
complement
proteins
was
performed
by
The
Center
for
Blood
Research
Laboratories,
Boston,
MA,
under
the
direction
of
Dr
David
H.
Bing,
using
previously
described
techniques
(Marcus
&
Alper,
1986).
Serum
samples
were
incubated
with
neuraminidase
from
Clostridium
perfringens
overnight
at
room
temperature
with
continuous
dialysis
against
0-1
M
phosphate
buffer,
pH
7
0,
containing
0{005
M
EDTA-Na2.
The
desialated
samples
were
subjected
to
electrophoresis
and
immunofixation
with
goat
anti-human
C4
(Atlantic
Antibodies,
Scarborough,
ME)
at
1
%
and
subjected
to
crossed
immunoelectrophoresis.
Some
samples,
processed
as
above,
were
developed
with
a
C4
complement
overlay
consisting
of
antibody-sensitized
sheep
erythrocytes
and
C4-
deficient
guinea
pig
serum
incorporated
into
a
gel
and
layered
onto
a
C4
agarose
gel.
The
presence
of
null
alleles
(QO)
was
determined
by
inspection
of
immunofixation
patterns
or
by
crossed
immunoelectrophoresis.
The
detection
of
null
alleles
in
heterozygotes
requires
the
quantification
of
all
gene
products
and
analyses
of
their
ratios.
This
allowed
identification
of
genuine
null
alleles
and
reduced
the
likelihood
of
an
incorrect
assignment
of
a
null
allele
that
may
have
resulted
from
an
ambiguous
situation
such
as
the
expression
of
the
same
C4
allotype
at
both
C4
loci.
BF
typing
was
carried
out
with
frozen
plasma
that
was
subjected
to
electrophoresis
in
agarose
gel
and
immunofixation
with
goat
antiserum
to
human
factor
B
(Atlantic
Antibodies)
as
previously
described.
Typing
for
the
C2
complement
proteins
was
performed
by
isoelectric
focusing
of
the
samples
in
polyacrylamide
gel
and
an
overlay
agarose
gel
containing
antibody-sensitized
sheep
erythrocytes
and
diluted
fresh
normal
human
serum.
Data
were
analysed
by
x2
analysis
with
2
x
2
contigency
tables.
RESULTS
Genotypes
of
the
complement
alleles
BF,
C2,
C4A
and
C4B
in
autistic
subjects
and
family
members
are
given
in
Table
1.
A
summary
of
the
C4A
and
C4B
typing
is
presented
in
Table
2.
Overall,
the
gene
frequency
of
the
C4A
null
allele
was
not
significantly
changed
in
any
of
the
autistic
subjects
or
any
of
their
family
members,
compared
with
the
normal
controls.
However,
the
gene
frequency
of
the
C4B
null
allele
was
significantly
increased
in
the
autistic
subjects
(P=0
03,
by
x2
contingency
table
analysis).
Moreover,
the
mothers
of
the
autistic
subjects
had
a
gene
frequency
of
C4B
that
was
also
elevated
(P=0-01).
On
a
phenotypic
basis,
11
out
of
the
19
(58%)
autistic
subjects
and
11
out
of
the
19
mothers
had
the
C4B
null
allele
on
one
of
their
chromosomes
as
compared
with
that
of
17
out
of
64
(27%)
of
the
unrelated
normal
subjects
(P=
0-14
in
both
cases).
The
siblings
had
a
frequency
of
the
C4B
null
allele
which
was
increased
(Table
2),
but
not
significantly;
the
paternal
frequency
for
C4B
was
not
elevated.
The
frequency
of
BF
and
C2
alleles
are
given
in
Table
3.
No
alteration
in
frequencies
with
any
of
these
alleles
was
found.
DISCUSSION
This
study
provides
preliminary
evidence
for
a
temporal
link
between
the
C4B
null
allele
and
autism.
Statistically
significant
findings
were
obtained,
although
the
study
included
only
a
limited
number
of
subjects.
Moreover,
comparison
of
the
Table
1.
Complement
alleles
in
family
members
of
autistic
subjects
Chromosomes
from
mothers
Chromosomes
from
fathers
BF-C2-C4A-C4B*
BF-C2-C4A-C4B*
Subject
No.
I
No.
2
No.
1
No.
2
no.
(autistic)t
(other)
(autistic)t
(other)
1
S-C-3-QO
S-C-6-1
S-C-3-1
S-C-3-1
2
S-C-2-(2,l)t
S-C-3-QO
S-C-3-1
S-C-QO-
1
3
S-C-3-QO
S-C-QO-l
S-C-QO-J
S-C-3-1
4
S-C-QO-3
S-C-3-QO
S-C-3-2
S-C-QO-
1
5
S-C-3-QO
FlC-QO-I
S-C-QO-I
S-C-3-1
6
S-C-3-1
S-C-3-1
S-C-3-1
S-C-QO-3
7
S-C-3-QO
S-C-3-1
S-C-QO-
I
F-C-3-1
8
S-C-QO-I
S-C-3-1
S-C-3-2
S-C-QO-l
9
S-C-6-1
S-C-QO-2
S-C-3-QO
S-C-QO-I
10
F-C-3-1
S-C-3-1
S-C-3-1
S-C-3-QO
11
F-C-3-1
S-C-QO-2
S-C-3-QO
F-C-3-1
12
S-C-QO-I
S-C-6-1
F-C-3-QO
F-C-3-1
13
F-C-3-1
S-C-3-QO
F-C-(3,2)-QO§
F-C-3-1
14
S-C-6-1
S-C-3-QO
S-C-3-1
F-C-2-QO
15
S-C-QO-
I
F-C-3-1
S-C-3-
1
S-C-3-1
16
S-C-3-QO
F-C-3-1
F-C-3-1
S-C-QO-I
17
S-C-3-1
S-?-4-2
S-C-6-1
F-C-3-1
18
S-C-3-QO
S-C-3-QO
S-?-4-5
S-C-3-1
19
S-C-3-QO
S-C-3-1
S-C-3-1
S-C-3-1
Alleles
received
by
normal
siblings
are
italicized.
*
Complement
alleles
given
in
order
of
BF-C2-C4A-C4B.
t
Alleles
segregating
to
autistic
children
presented
as
maternal
and
paternal
chromosomes
number
1.
I
Expressed
the
relatively
common
duplicated
C4B
allele
(2,1).
§
Expressed
the
duplicated
C4A
allele
(3,2).
Table
2.
C4
Complement
types
in
families
of
autistic
subjects
Number
with
complement
type
and
gene
frequency
Autistic
Sibling
Maternal
Paternal
Normal
C4
Type
(n
=
38)
(n
=
28)
(n
=
38)
(n
=
38)
(n
=
124)
C4A
1
0
(0-00)
0
(0-00)
0
(0-00)
0
(0-00)
1
(0-01)
2
2
(0
05)
1
(0-04)
1
(0
03)
3
(0-08)
4
(0
03)
3
26
(0-68)
15
(0
54)
24
(0-63)
26
(0-68)
74
(0
60)
4
1
(0-03)
2
(0
07)
1
(0
03)
1
(0-03)
17
(0
14)
6
3
(0
08)
3
(0
11)
4
(0
11)
1
(0
03)
3
(0-02)
QO
7
(0
18)
7
(0
25)
8
(0
21)
8
(0
21)
25
(0
20)
C4B
1
23
(0
61)
17
(0-61)
22
(0
58)
28
(0
74)
89
(0
72)
2
3(008)
3(0
11)
4(0-11)
2(005)
15(0-12)
3
1
(0
03)
0
(0
00)
1
(0
03)
1
(0
03)
1
(0
01)
5
1
(0-03)
1
(0-04)
0
(0
00)
1
(0
03)
2
(0
02)
QO
11(0.29)*
7(025)
12(032)t
6(0-16)
17(0
14)
*
P=003.
t
P=0
01.
439
Page 2
440
R.
P.
Warren
et
al.
Table
3.
BF
and
C2
alleles
in
families
of
autistic
subjects
Number
with
allele
and
gene
frequency
Autistic
Sibling
Maternal
Paternal
Normal
Component
(n
=38)
(n
=28)
(n
=38)
(n?=
38)
(n=
124)
BF
S
32
(0
84)
23
(0-82)
32
(0
84)
29
(0
76)
101
(0
81)
F
6
(0
16)
5
(0
18)
5
(0
13)
9
(0-24)
18
(0
15)
Fl
0
(0
00)
0
(000)
1
(0-03)
0
(0
00)
3
(002)
SI
0
(0
00)
0
(0
00)
0
(0
00)
0
(0
00)
2
(0
02)
C2*
C
37
(0
97)
26
(0
93)
37
(0
97)
37
(0
97)
116
(0
94)
B
0
(000)
0
(000)
0
(000)
0
(000)
I
(001)
*C2
typing
on
chromosomes
of
one
autistic
subject,
two
siblings,
one
mother,
one
father
and
seven
normal
subjects
was
uninterpretable.
frequency
of
the
C4B
null
frequency
in
our
normal
unrelated
subjects
(27%,)
with
that
reported
in
the
literature
(30%X,)
(reviewed
by
Kahl
&
Atkinson,
1988)
provides
additional
support
for
a
link
between
the
C4B
null
allele
and
autism.
However,
these
findings
must
be
interpreted
with
caution
because
11
out
of
the
mothers
as
well
as
four
out
of
the
siblings,
three
of
whom
were
younger
than
the
autistic
subjects,
all
without
the
symptoms
of
autism,
expressed
the
C4B
null
allele.
Therefore,
aetiological
agents,
in
addition
to
the
possible
involvement
of
the
C4B
null
allele,
must
be
responsible
for
the
development
of
autism.
For
example,
as
reviewed
above,
viral
infections
and
immune
abnormalities
also
have
been
associated
with
autism.
Thus,
it
is
possible
that
a
combination
of
a
C4B
null
allele,
a
virus,
an
immune
element
and/or
other
agents
interact
in
causing
this
severe
developmental
disorder.
Due
to
preliminary
nature
of
this
report,
it
would
probably
be
premature
to
present
an
extensive
discussion
on
the
possible
mechanism
by
which
partial
deficiency
of
C4
complement
proteins
predisposes
to
autism.
However,
one
could
speculate
that
complement
deficiency
allows
an
infectious
agent
or
immune
complex
to
persist,
resulting
in
prolonged
immunologi-
cal
stimulus
and
triggering
of
an
autoimmune
reaction.
The
fact
that
the
mothers
of
the
autistic
children
expressed
the
C4B
null
allele
at
the
same
frequency
as
their
autistic
children
might
imply
that
a
partial
maternal
complement
deficiency
also
contributes
to
the
development
of
some
cases
of
autism.
Perhaps,
during
the
time
that
the
mother
was
carrying
the
autistic
child,
she
did
not
clear
a
viral
infection
in
immunocompetent
fashion,
resulting
in
an
intrauterine
fetal
infection
that
damaged
the
developing
central
nervous
system
or
triggered
an
autoimmune
response.
Cireumstantial
evidence
for
this
possibility
are
reports
of
association
of
congenital
infections
of
rubella
(Chess,
1977)
and
cytomegalovirus
(Stubbs,
1978)
with
autism.
Another
possible
explanation
for
an
association
of
the
C4B
null
allele
with
autism
is
by
virtue
of
the
location
of
the
structural
gene
for
this
allele
within
the
major
histocompatibi-
lity
complex
on
chromosome
6.
The
null
allele
of
C4B
has
been
reported
to
be
strong
linkage
disequilibrium
with
HLA-DR4
and
HLA-B44
(Awdeh
et
al.,
1983).
Perhaps
one
of
these
alleles
or
some
other
gene
linked
to
C4B
is
related
to
the
development
of
autism.
Our
preliminary
findings
suggest
that
a
thorough
investigation
is
needed
into
major
histocompatibility
markers
in
autism.
ACKNOWLEDGMENTS
Supported
by
grant
MH42119
from
the
National
Institute
of
Mental
Health
and
a
grant
from
the
Willard
L.
Eccles
Charitable
Foundation.
The
authors
express
appreciation
to
P.
Brent
Peterson,
MD,
and
the
Children's
Behavior
Therapy
Unit,
Salt
Lake
City,
Utah,
for
assisting
in
identification
of
patients
and
establishing
the
diagnosis
of
autism,
and
Ms
Rosanne
Stein
and
David
H.
Bing,
PhD,
Center
for
Blood
Research,
for
performing
the
complotyping.
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Page 3
  • Source
    • "Furthermore, strong association of the complement C4B null allele in HLA class III region with autism has been reported in several studies [40]. They demonstrated a significant increase in the C4B null allele in autistic children compared to controls505152. Moreover, Mostafa et al. reported an increased risk of autism in the families with autoimmune disorders [52]. "
    Full-text · Article · Jan 2015
  • Source
    • "The A * 02-B * 44 haplotype is part of the larger B44-SC30-DR4 extended haplotype, which is more frequent in autistic children than in controls [14, 20]. This extended haplotype also contains two genetic loci previously shown to be associated with autism, the C4B null allele, and HLA-DR4 [15, 21, 39]. In class II, we found a positive association between DRB1 * 11 allele and autism, similar to the findings of a study from Egypt [31]. "
    [Show abstract] [Hide abstract] ABSTRACT: Earlier reports showed the relationship between autism and immune genes located in the human leukocyte antigen (HLA). In this current study, we compared the HLA class I and class II alleles and haplotypes in 35 autistic children with 100 control subjects from Saudi Arabia, using PCR-SSP method and Luminex technology. In class I the HLA-A*01 (P = 0.03, OR 2.68), A*02 (P = 0.001, OR 3.02) and HLA-B*07 (P = 0.01, OR 3.27), were significantly associated with autism. Also, the haplotype A*02-B*07 was significantly higher in autistic patients than in controls (P = 0.007, OR 5.83). In class II, DRB1*1104 was significantly higher in patients than in controls (P = 0.001, OR 8.75). The DQB1*0202 (P = 0.001, OR 0.24), DQB1*0302 (P = 0.001, OR 0.14), and DQB1*0501 (P = 0.012, OR 0.25), were negatively associated with disease. While the four-loci genotype study showed that A*01-B*07-DRB1*0701-DQB1*0602 (P = 0.001, OR 41.9) and the A*31-B*51-DRB1*0103-DQB1*0302 (P = 0.012, OR 4.8) are positively associated with autism among Saudi patients. This is the first report on a foreseeable risk of association of HLA-B*07 allele with autism. Thus, HLA-B*07 allele and the closely linked haplotype A*01 B*07 DRB1*0701 DQB1*0602 may serve as a marker for genetic susceptibility to autism in Saudis.
    Full-text · Article · Feb 2014
  • Source
    • ". In terms of MHC class III genes, the C4 complement alleles have been linked to ASD [34] [35]. "
    [Show abstract] [Hide abstract] ABSTRACT: Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.
    Full-text · Article · Jul 2013 · Journal of Autoimmunity
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