A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity
Maria Luisa Conte
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Aida M. Bertoli-Avella
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Bianca M. de Graaf
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Francesca Punzo
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Giuliana Lama
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Angela La Manna
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Carolina Grassia
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Pier Francesco Rambaldi
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Ben A. Oostra
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Silverio Perrotta
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P. F. Rambaldi Department of Radiological Sciences, Nuclear Medicine, Second University of Naples
, Naples,
Italy
Vesicoureteral reflux (VUR) is the most common disease of the urinary tract in children. In order to identify gene(s) involved in this complex disorder, we performed a genome-wide search in a selected sample of 31 patients with primary VUR from eight families originating from southern Italy. Sixteen additional families with 41 patients were included in a second stage. Nonparametric, affected-only linkage analysis identified four genomic areas on chromosomes 1, 3, and 4 (p <0.05); the best result corresponded to the D3S3681-D3S1569 interval on chromosome 3 (nonparametric linkage score, NPL= 2.75, p = 0.008). This region was then saturated with 26 additional markers, tested in the complete group of 72 patients from 24 families (NPL= 2.01, p = 0.01). We identified a genomic area on 3q22.2-23, where 26 patients from six multiplex families shared overlapping haplotypes. However, we did not find Financial support: This work was in part supported by the Nierstichting Nederland (grant number C05.2146) and Fondo per gli Investimenti della Ricerca di Base (FIRB).
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Vesicoureteral reflux (VUR) (OMIM 193000) is the most
common disease of the urinary tract in children and
affects 12% of the Caucasian population [1]. VUR may
be associated with both acquired postinfectious and
congenital parenchymal damage, currently known as
reflux nephropathy (RN) [2, 3]. The most serious
consequence of RN is chronic renal insufficiency (CRI),
leading to end-stage renal failure (ESRF), dialysis, and/or
renal transplantation: 25.4% of children affected with CRI
have RN [4]. As a consequence, the impact of VUR on
public health is considerable and, despite medical and
surgical interventions for the past decades, the incidence
of VUR-related renal failure has not decreased [5].
The reflux may occur isolated or in association with
other congenital abnormalities of kidney/urinary tract
(CAKUT) or as part of syndromic entities, such as
renalcoloboma or branchio-oto-renal syndromes [68]. The
exact etiology of primary VUR is not known, but it is
probably related to an abnormal morphogenesis of the
ureteral bud, leading to a defect of the ureterovesical
junction [9]. The initial evidence suggesting a genetic
origin of primary VUR came from twin studies, showing an
80100% concordance for VUR in monozygotic twins vs. a
3550% concordance in dizygotic twins [10, 11].
Subsequent evidence included familial clustering of VUR [12],
ethnic differences between affected and nonaffected
individuals [13], and an increased risk (3050%) of
developing VUR in first-degree relatives of an index case
[1416]. From family studies, a range of inheritance
patterns was reported, including autosomal dominant with
incomplete penetrance [1720], autosomal recessive [21],
polygenic [22], and even X-linked [23].
Previous studies suggest a urinary tract malformation
locus on chromosome 6p [24, 25]. Studies of humans with
chromosomal abnormalities also suggest candidate loci or
genes on chromosomes 10q26 [26], 19q13 (USF2 gene)
[27], and 13q3334 [28]. Because mutations in PAX2 on
10q24 cause renal-coloboma syndrome, a rare autosomal
dominant disease with kidney anomalies that include VUR,
this gene was also proposed as a candidate [6, 7]. However,
none of these loci or genes has been shown causally related
to primary VUR [19, 20]. Recently, Lu et al. [29] showed
that mutations in the ROBO2 gene contribute to the
pathogenesis of VUR/CAKUT in a small proportion of
families. In the only genome-wide linkage study reported to
date, Feather et al. [18] demonstrated linkage to
chromosome 1p13 for primary VUR under a model of autosomal
dominant inheritance with reduced penetrance.
Here, we describe the results of the second genome-wide
scan for primary VUR. Differently from previous studies
and aiming to collect a homogeneous sample set, our
patients were ascertained in a single geographic region. Our
results suggest the presence of several novel loci for
primary VUR, giving further evidence for the genetic
heterogeneity of this disorder.
Patients and families
Fifty-one pedigrees with multiple patients with VUR coming
from Campania (southern Italy) were enrolled in the study
(Fig. 1). All families were ascertained through an index case,
with VUR documented by voiding cystourethrography
(VCUG) in males and direct radionuclide cystography
(RNC) in females and family members. Three pediatric
nephrologists and one radiologist assessed the patients. RN
was diagnosed by DMSA scintigraphy (dimercaptosuccinic
acid labeled with Technetium-99 m) and defined as focal
defects of radionuclide uptake and/or by one-kidney
differential uptake below 43% [30]. VUR grading was
made accordi (...truncated)