Mutation in Mitochondrial Gene Associated with Progressive Kidney ...

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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