Download Autosomal dominant medullary cystic kidney disease: evidence of

Nephrol Dial Transplant (1998) 13: 1955–1957
Nephrology
Dialysis
Transplantation
Rapid Communication
Autosomal dominant medullary cystic kidney disease: evidence of
gene locus heterogeneity
Arno Fuchshuber1, C. Constantinou Deltas2, Silke Berthold1, Christoforos Stavrou3,
Martin Vollmer1, Christopher Burton4, Terry Feest4, Detlef Krieter5, Andreas Gal6,
Matthias Brandis1, Alkis Pierides3, and Friedhelm Hildebrandt1
1University Children’s Hospital, Freiburg, Germany, 2The Cyprus Institute of Neurology and Genetics, Deptartment of
Molecular Genetics, Nicosia, 3Department of Nephrology, Ministry of Health, Nicosia, Cyprus, 4Southmead Hospital,
The Richard Bright Renal Unit, Bristol, UK, 5University Hospital, Department of Nephrology and Rheumatology,
Göttingen, and 6University Hospital Eppendorf, Institute of Human Genetics, Hamburg, Germany
Abstract Autosomal dominant medullary cystic kidney
disease (ADMCKD; synonym: medullary cystic disease, MCD) is an autosomal dominant kidney disorder,
sharing morphological and clinical features with recessive juvenile nephronophthisis (NPH ), such as reduced
urinary concentration ability and multiple renal cysts
at the corticomedullary junction. While in NPH endstage renal disease ( ESRD) occurs in adolescence,
ADMCKD leads to ESRD in adulthood. Recently a
gene locus for ADMCKD has been localized to chromosome 1q21 in two large Cypriot families. This
prompted us to examine linkage in three ADMCKDfamilies, using the same set of polymorphic microsatellite markers spanning the critical region on chromosome 1q21. Haplotype analysis revealed that none of
the three families showed linkage to this locus, thus
demonstrating evidence for genetic locus heterogeneity.
Additional linkage analysis studies need to be performed in order to identify further gene loci cosegregating with this autosomal dominant kidney disorder.
Key words: autosomal dominant medullary cystic
kidney disease; chronic renal failure; haplotype
analysis; juvenile nephronophthisis; medullary cystic
disease
anaemia. Both ADMCKD and familial juvenile
nephronophthisis (NPH ), which is inherited as an
autosomal recessive trait, are part of the so-called
‘MCD/NPH-complex’. Renal morphology is similar in
both diseases, and is characterized by focal interstitial
fibrosis, irregular thickening of the tubular basement
membrane and bilateral renal cyst formation at the
corticomedullary junction. Since the pathoaetiology of
this hereditary disease complex is still unknown, the
best approach to identify the genes involved is positional cloning. Indeed a first gene (NPHP1) for this
disease complex has been identified for NPH type 1
[1,2]. This gene encodes an SH3 domain, found in a
great variety of membrane-associated or intracellular
proteins. Linkage studies showed no allelism between
ADMCKD and NPHP1 [3,4]. Recently, a gene locus
for ADMCKD has been localized by linkage analysis
on chromosome 1q21 in two large Cypriot families,
presenting with hyperuricaemia and gout [5]. We
report on linkage analysis, which we performed in
three additional ADMCKD-families originating from
Germany and Great Britain, using the same set of
polymorphic markers, which spans the critical genetic
region on chromosome 1q21.
Subjects and methods
Introduction
Autosomal dominant medullary cystic kidney disease
(ADMCKD) is an autosomal dominant cystic nephropathy leading to chronic renal failure, usually during
or after the fourth decade. Typical clinical symptoms
preceding renal failure are polyuria, polydipsia and
Correspondence and offprint requests to: C. Constantinou Deltas,
Pharm.R., PhD, The Cyprus Institute of Neurology and Genetics,
Department of Molecular Genetics, PO Box 3462, 6 International
Airport Avenue, Ayios Dhometios, 1683 Nicosia, Cyprus.
We have collected three large multiplex families, which
fulfilled the following diagnostic criteria for ADMCKD:
(i) pedigrees are consistent with autosomal dominant inheritance; (ii) affected individuals were present in three or more
generations; (iii) renal morphology of at least one affected
individual in each family was consistent with ADMCKD.
The pedigrees are shown in Figure 1. The ages at terminal
renal failure ranged between 31 and 40 years in family MCD5
and between 37 and 55 years in family MCD3, suggesting
both intra- and interfamilial variability. Neither hyperuricaemia nor other extrarenal symptoms were reported in any
affected individual.
In total, 39 individuals including 14 affected patients
© 1998 European Renal Association–European Dialysis and Transplant Association
1956
A. Fuchshuber et al.
Fig. 1. Haplotype analyses with nine consecutive microsatellite markers spanning the critical genetic region on chromosome 1q21. Affected
individuals are indicated by black symbols. Males are shown as squares, females as circles. Patients in which penetrance could not be
excluded are indicated by a question mark. Haplotype data were obtained using the following marker order: D1S1156, D1S514, D1S498,
D1S1153, D1S1595, D1S2125, D1S1653, D1S1679 and D1S1655. The paternal haplotype of every individual is represented by the left bar,
the maternal haplotype by the right bar.
Gene locus heterogeneity in autosomal dominant medullary cystic kidney disease
where haplotyped by using eight consecutive polymorphic
microsatellite DNA markers spanning a genetic region of
approximately 8 cM, as reported by Christodoulou et al.
(5). Since penetrance of the disease is age dependent, the
probability of clinically healthy subjects of being affected
was calculated using age-related liability classes. Patients
under the age of 20 years were not included. The order of
the tested marker loci was centromere – D1S514 – D1S498
– D1S1153 – D1S1595 – D1S2125– D1S1653 – D1S1679 –
D1S1655 – telomere (flanking markers are underlined ) [5].
Results and discussion
Haplotype analysis revealed that none of the haplotypes identified around the gene locus on chromosome
1q21 cosegregated with the disease phenotype
(Figure 1). Therefore, this chromosomal region could
be excluded as a candidate gene locus in these families.
The results demonstrate genetic heterogeneity in
ADMCKD.
As pointed out by Christodoulou et al., both of the
families they investigated shared the same affected
haplotype, thus suggesting a founder effect in this
Cypriot population [5]. Considering the clinical variants of ADMCKD, especially the variability of onset
1957
of chronic renal failure and the association of nonrenal manifestations like hyperuricemia or gout, the
existence of gene locus heterogeneity in ADMCKD is
not surprising. The identification of further gene loci
for ADMCKD will help to elucidate the pathogenesis
of this genetically heterogeneous cystic nephropathy.
References
1. Hildebrandt F, Otto E, Rensing C et al. A novel gene encoding
an SH3 domain protein is mutated in nephronophthisis type 1.
Nature Genet 1998; 17: 149–153
2. Saunier S, Colado J, Heilig R et al. A novel gene that encodes a
protein with a putative src homology 3 domain is a candidate
gene for familial juvenile nephronophthisis. Hum Mol Genet,
1997; 6: 2317–2323
3. Stavrou C, Pierides A, Zouvani I et al. Medullary cystic kidney
disease with hyperuricemia and gout in adults of a large Cypriot
family. No allelism with nephronophthisis type 1. Am J Med
Genet 1998; 77: 149–154
4. Scolari F, Ghiggeri GM, Casari G et al. Autosomal Dominant
Nephronophthisis/Medullary Cystic Disease: a disorder with variable clinical pictures and absence of linkage with the NPH1 locus
(submitted)
5. Christodoulou K, Tsingis M, Stavrou C et al. Chromosome 1
localization of a gene for autosomal dominant medullary cystic
kidney disease (ADMCKD). Hum Mol Genet 1998; 7: 905–911
Received for publication: 8.6.98
Accepted: 10.6.98