induced diabetes after kidney transplantation for end-stage renal failure. This suggests that primary kidney disease with progressive renal failure may represent.
Mutation in Mitochondrial with Progressive Kidney
Gene
tRNALeu
Disease
JANNA J. JANSEN,* J. ANTONIE MAASSEN,t HENNY A. J. LEMMINK, JODY M. W. VAN LEEN M. ‘T HART,t HUBERT J. M. SMEETS, HERMAN H. P. J. LEMKES* Departments
of *Metabolic
1Pathology,
University
University
Abstract.
Several
studies
Diseases
Hospital
Hospital
show
an association
maternally
This
mutation
sion
as
shows
is
from
Screening
performed
University
diabetes
heterogeneity
apparent
syndromes. was
inherited its
in those Hospital
diabetic
diabetics
with
-
for
several
attending
the Leiden
who
had
a history
of ma-
ternably inherited diabetes, sensonineural hearing loss, or both. Four individuals from three unrelated families were identified who suffered from progressive nondiabetic kidney disease in association
with
of inheritance
diabetes
melbitus
suggested
Previously,
maternal
we reported and
deafness
(A 0) (mtDNA)
transition at position (1 ,2). Subsequently,
approximately and Japan in
most
populations
with
lactic
unknown,
(mixtures or effects We tients
variations
in
re-evaluated
the
outpatient
inherited
the
episodes)
mtDNA have
postrenal
in expression of this phenomenon
of
hearing mutation
patients
diabetic
a history
from
loss,
paof
ma-
or both,
one of the heteroplasmy
3, 1997.
Accepted
March
22,
(J Am
renal failure. progressive typical
Materials attending maternal revealed
Society
ondary
of the
patients disease
to steroid
3243
mtDNA
from was
patients data
124,
found. Alport
showed show the by in
the the
1997)
Remarkably, syndrome,
kidney a third
mtDNA
mutation.
mutation
in those
three
treatment
after
three
1). Nine family
(Figure
lineage
hearing
loss,
and
and
three of although steroidend-stage
disease with major pheno-
diabetic
patients
was
examined
fast, venous glycosylated glucose
members
reported
blood
by
Their history
clinical
the
re-
all in
disease,
in glucose
assessing
sec-
was
four probands.
of clinical
in
only
ratio
were
homeostaof albumin
sample (8). A complete medical history height, and weight were measured. A for the presence
samples
hemoglobin tolerance
changes
history
was
family
of these
to be free
disease
a medical
diabetes
transplantation.
A detailed
of the mutation, kidney
had and
renal
below.
in a fasting urine and blood pressure,
sediment
75-g
given
for presence
families
predominant
corded
oral
8: 1 1 18-1
was with
are
glucose, of Nephrobogy
in heteroplasrelatives. Also,
and Methods
female
overnight
American
Nephrol
for the 3243
kidney
urine
DNA of the
the Leiden University Hospital diabetes clinic who had a family history of diabetes, sensorineural hearing loss, or both 15 positive individuals from 14 families. Of these, four
positive
sis,
as in
patients
is characterized at position 3243
This suggests that primary renal failure may represent
expression
which
63 unrelated
had never been present. They developed diabetes after kidney transplantation for
1046-6673/0807-I 1 18$03.00/0 Journal of the American Society by the
Soc
disease that 0 mutation
families, the mutation had been diagnosed
hematunia induced
another
suspected Alport syndrome for the 3243 mutation. These
mtDNA.
Correspondence to Dr. Janna J. Jansen, University Hospital Leiden, Department of Metabcdic Diseases and Endocrinology. Building 1, C4-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
(ii) 1997
Genetics,
The mutation was detected patients and their maternal
of a kidney of the A -
to creatinine was taken,
Copyright
families,
characteristics
1997.
of Nephrology
three
existence presence
screened March
and
of Human
and from the 63 additional Alport syndrome examined for the presence of the 3243A -p 0
63
the maternal
Received
and
tNephrology,
Department
in mtDNA.
unre-
BRUIJN,’1
Alport syndrome were selected at random. blood and other tissues from members
in mtDNA. in the four
Screening
heteroplasmy
had
3243
transplant
en-
in-
in those
who
of the
(3,4) present
at a cellular level) been suggested.
of diabetes
mutation mic form
lated them
(7),
tissue-specific
sensonineural
presence
Europe
(myopathy,
strokelike
department
diabetes,
for
female
type
combina-
is also
syndrome
and
of wild-type and mutant of the nuclear background
screening
In four
MELAS
in both mutation
phenotypic heterogeneity pathophysiobogical basis
but
in our
ternably by
the
acidosis,
The
mode
in the mitochondnial DNA mutation was identified in
the same
dicating a striking the mutation. The is
3243 this
The
of maternally inherited a guanine for adenine
Interestingly,
patients
loss.
transmission.
I % of diabetic (5,6).
cephalopathy,
hearing
the association (MIDD) with
diabetes -
and
to these
possible peripheral
three families patients was
other
in mtDNA
and
WOUDE,
tion of renal failure and hearing boss had been misdiagnosed Alport syndrome in three of the four individuals. Therefore, with from
expres-
DER
Biochemistry,
Netherlands;
addition
0 mutation
patients clinic
Netherlands.
(MIDD).
phenotypic
association
for the 3243A
The
of a guanine
in its
tMedical
The
in mitochondnial diabetic subtype
and deafness
FOKKO J. VAN DEN OUWELAND,1 JAN ANTHONIE
Endocrinology, Leiden,
Nijmegen,
-
designated
and
Leiden,
Nijmegen,
adenine substitution (A 0) at position 3243 DNA (mtDNA) with a recently recognized
Associated
test
(HbAbc), was
of hematuria.
were collected performed.
and
After
for assessment creatinine,
and
an
of an
mtDNA
Glycosylated
hemoglobin
method.
The
normal
albumin
excretion
nephebometry nine
was
system
was
assessed
(HbAlc)
range
for
by
limit
determined
method
assessed
(upper
was
this
to 6.3%.
Urinary
of
a kinetic
“rate”-
methods
of normal
by an autoanalyzer
by an HPLC
is 4.3
of
