Characterization of the murine polycystic kidney disease (Pkd2) gene
Institut fu¨r Humangenetik, Westfa¨lische Wilhelms-Universita¨t Muenster, Vesaliusweg 12-14, 48149 Mu¨nster, Germany
Abteilung medizinische Genetik der Universita¨t Ulm, Albert-Einstein-Allee 11, 89069 Ulm, Germany
Received: 13 March 1998 / Accepted: 11 May 1998
Abstract. Autosomal dominant polycystic kidney disease
(ADPKD) is one of the most frequent genetically transmitted dis-
orders among Europeans with an attributed frequency of 0.1%.
The two most common genetic determinants for ADPKD are the
PKD1 and PKD2 genes.
In this study we report the genomic structure and pattern of
expression of the Pkd2 gene, the murine homolog of the human
PKD2 gene. Pkd2 is localized on mouse Chromosome (Chr) 5
proximal to anchor marker D5Mit175, spans at least 35 kb of the
mouse genome, and consists of 15 exons. Its translation product
consists of 966 amino acids, and the peptide shows a 95% homol-
ogy to human polycystin2. Functional domains are particularly
well conserved in the mouse homolog. The expression of mouse
polycystin2 in the developing embryo at day 12.5 post conception
is localized in mesenchymally derived structures. In the adult
mouse, the protein is mostly expressed in kidney, which suggests
its functional relevance for this organ.
Human polycystic kidney diseases (PKD) form a family of closely
related renal disorders which genetically can be divided into two
major groups: the autosomal recessive (ARPKD) and the autoso-
mal dominant (ADPKD) forms. ADPKD is one of the most com-
monly inherited diseases with an attributed frequency of 1 in 400
to 1 in 1000 in Caucasians. It is generally characterized by pro-
gressive development and enlargement of multiple fluid-filled
cysts in the kidneys that frequently result in chronic and end-stage
renal failure. ADPKD accounts for about 8–12% of all patients
requiring hemodialysis world-wide (Gabow 1993). However, it is
not only restricted to the kidneys but can also manifest as a mul-
tisystem disorder, with symptoms including hepatic cysts, cardio-
vascular valve abnormalities, pancreatic cysts, cerebral aneurysms,
and colonic diverticula (Gabow 1990).
So far, two genes, PKD1 and PKD2, have been identified as
causative determinants for the disease, and there is convincing
evidence that at least a third ADPKD locus yet to be mapped is
also involved (de Almeida et al. 1995; Bogdanova et al. 1995). For
the Northern European population, an ADPKD frequency of about
85% is attributed to PKD1 and about 14% to PKD2 (Peters and
Sandkuijl 1992). Both types of disease exhibit almost identical
clinical features although in general PKD2 families seem to show
a milder clinical development of the disease condition (Ravine et
The human PKD2 gene was mapped in 1993 (Kimberling et al.
1993; Peters et al. 1993) and identified and partly characterized in
1996 (Mochizuki et al. 1996). It is a single-copy gene located on
Chr 4q21-q23. The genomic structure of the human PKD2 gene
has recently been published (Hayashi et al. 1997). The PKD2 gene
is encoded in at least 15 exons covering over 68 kb of the genome.
It generates a transcript of 5.4 kb, which is expressed in most
tissues. The translation product of PKD2, polycystin2, has a pre-
dicted length of 968 amino acids and a calculated molecular mass
of 110 kDa. The modeling data suggest that polycystin2 as pro-
posed for polycystin1 is an integral membrane protein; it has six
transmembrane domains and intracellular localization of the car-
boxy- and the amino-termini.
Polycystin2 has significant homology to the voltage-activated
, and its identity to polycystin1 is roughly 25%,
having an overall similarity of 50%. Both PKD proteins are
thought to be part of the same or parallel signal transduction path-
ways which may be involved in tubular morphogenesis. Recent
data show physical interactions between the C-termini of the two
proteins in vivo. Recent progress towards understanding the patho-
physiology of ADPKD casts a new light upon cyst formation. It
has been shown that cyst expansion in this case is characterized by
altered growth responses, abnormal expression of proteins, and
changes in polarity of affected epithelia (Wilson 1991; Wilson et
al. 1991). All these changes may be signs of de-differentiation of
the tubular epithelial cells, which leads to the development of
cysts. However, the nature of the primary defect triggering those
changes still remains obscure.
For study of the disease-causing mechanisms for ADPKD in
more detail and the interactions of the responsible gene products,
it is evidently beneficial to develop animal models that are insuf-
ficient in one or both gene functions. Such models are currently
available only for the condition of autosomal recessive polycystic
kidney disease (ARPKD), a rat model which is neither ADPKD1
nor ADPKD2 (Simon et al. 1994; Iakoubova et al. 1995; Bihoreau
et al. 1997), and a form of ADPKD in Persian cats (Biller et al.
1996; Eaton et al. 1997). Therefore, it seems to be important to
study the animal homologs of the known ADPKD genes. During
preparation of this manuscript the cDNA sequence of the murine
Pkd2 was published (Wu et al. 1997). The cloned cDNA sequence
is predicted to encode a highly conserved 966-amino-acid protein
with 91% identity and 98% similarity to human polycystin-2 at the
amino acid level. Here we report the genomic structure, the ex-
pression pattern, and the refined mapping of Pkd2, the murine
homolog of the human PKD2 gene.
Materials and methods
Identification of mouse cDNA and BAC genomic clones.
cDNA clones homologous to PKD2 cDNA (EMBL/GenBank Accession
No. U 50928) were identified by performing a homology search with the
TBLASTX algorithm. The sequence of two clones, AA023786
(IMAGp998F061077) and W11044 (IMAGp998F19715) from library No.
998 of the I.M.A.G.E. consortium, showed a high degree of homology to
the human PKD2 gene sequence; both clones were obtained from the
Resource Center of the German Human Genome Project (Max-Planck
Correspondence: B. Dworniczak
Sequence data from this article have been deposited with the EMBL/
GenBank Data libraries under Accession Nos. Y13278, Y14105-Y14120.
Mammalian Genome 9, 749–752 (1998).
© Springer-Verlag New York Inc. 1998