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Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.
[zellweger syndrome]
Peroxisomes
are
subcellular
organelles
involved
in
lipid
metabolic
processes
,
including
those
of
very
-
long
-chain
fatty
acids
and
branched-chain
fatty
acids
,
among
others
.
Peroxisome
matrix
proteins
are
synthesized
in
the
cytoplasm
.
Targeting
signals
(
PTS
or
peroxisomal
targeting
signal
)
at
the
C-
terminus
(
PTS
1
)
or
N-
terminus
(
PTS
2
)
of
peroxisomal
matrix
proteins
mediate
their
import
into
the
organelle
.
In
the
case
of
PTS
2
-
containing
proteins
,
the
PTS
2
signal
is
cleaved
from
the
protein
when
transported
into
peroxisomes
.
The
functional
mechanism
of
PTS
2
processing
,
however
,
is
poorly
understood
.
Previously
we
identified
Tysnd
1
(
Trypsin
domain
containing
1
)
and
biochemically
characterized
it
as
a
peroxisomal
cysteine
endopeptidase
that
directly
processes
PTS
2
-
containing
prethiolase
Acaa
1
and
PTS
1
-
containing
Acox
1
,
Hsd
17
b
4
,
and
ScpX
.
The
latter
three
enzymes
are
crucial
components
of
the
very
-
long
-chain
fatty
acids
β-oxidation
pathway
.
To
clarify
the
in
vivo
functions
and
physiological
role
of
Tysnd
1
,
we
analyzed
the
phenotype
of
Tysnd
1
(
-
/
-
)
mice
.
Male
Tysnd
1
(
-
/
-
)
mice
are
infertile
,
and
the
epididymal
sperms
lack
the
acrosomal
cap
.
These
phenotypic
features
are
most
likely
the
result
of
changes
in
the
molecular
species
composition
of
choline
and
ethanolamine
plasmalogens
.
Tysnd
1
(
-
/
-
)
mice
also
developed
liver
dysfunctions
when
the
phytanic
acid
precursor
phytol
was
orally
administered
.
Phyh
and
Agps
are
known
PTS
2
-
containing
proteins
,
but
were
identified
as
novel
Tysnd
1
substrates
.
Loss
of
Tysnd
1
interferes
with
the
peroxisomal
localization
of
Acaa
1
,
Phyh
,
and
Agps
,
which
might
cause
the
mild
Zellweger
syndrome
spectrum-resembling
phenotypes
.
Our
data
established
that
peroxisomal
processing
protease
Tysnd
1
is
necessary
to
mediate
the
physiological
functions
of
PTS
2
-
containing
substrates
.
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"functional mechanism"
symptom
zellweger syndrome
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