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Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup.
[cystinuria]
Cystinuria
is
an
inherited
disorder
of
a
renal
tubular
amino
acid
transporter
and
leads
to
increased
cystine
excretion
with
the
risk
of
urinary
stone
formation
.
Phenotypical
classification
is
based
on
urinary
amino
acid
concentration
as
type
I
(
silent
)
,
type
non-
I
(
hyper-excretors
)
,
mixed
or
untyped
.
Genotypic
classification
is
based
on
mutations
in
SLC
3
A
1
(
type
A
)
or
SLC
7
A
9
(
type
B
)
.
We
present
six
family
members
with
a
complex
phenotypic
profile
based
on
mutations
in
both
genes
.
The
index
patient
presents
a
known
homozygous
mutation
(
p
.
T
189
M
)
in
SLC
3
A
1
and
a
homozygous
mutation
(
c
.
225
C
 
>
 
T
)
in
SLC
7
A
9
.
Based
on
a
bioinformatics
analysis
and
published
findings
,
we
considered
p
.
T
189
M
to
be
pathogenic
and
initially
classified
c
.
225
C
 
>
 
T
as
a
silent
variant
.
However
,
segregation
analysis
detected
homozygosity
for
p
.
T
189
M
also
in
non-affected
individuals
,
whereas
homozygous
c
.
225
C
 
>
 
T
segregated
with
the
phenotype
.
RNA
studies
confirmed
c
.
225
C
 
>
 
T
to
cause
aberrant
splicing
.
Based
on
our
findings
,
we
conclude
that
c
.
225
C
 
>
 
T
in
SLC
7
A
9
determines
the
clinical
phenotype
in
this
family
,
whereas
additional
SLC
3
A
1
mutations
aggravate
the
phenotype
in
heterozygotes
for
c
.
225
C
 
>
 
T
in
SLC
7
A
9
without
resulting
in
cystinuria
in
the
homozygous
state
.
Our
results
underline
the
need
for
careful
biochemical
characterization
of
family
members
of
an
index
case
of
cystinuria
.
Genetic
analysis
of
both
cystinuria
genes
may
be
necessary
due
to
the
synergistic
effects
of
mutations
in
two
genes
.
