(Hypertension. 1999;34:187-191.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Genetic Isolation of a Chromosome 1 Region Affecting Susceptibility to Hypertension-Induced Renal Damage in the Spontaneously Hypertensive Rat
From the Department of Laboratory Medicine, University of California (E.S.L., T.W.K., W.L., N.W.), San Francisco, Calif; Departments of Internal Medicine and Pathology, Loyola University and Hines Veterans Administration Hospital (K.A.G., M.P., A.K.B.), Maywood, Ill; Department of Physiology, Wayne State University School of Medicine (M.C.C., P.C.C.), Detroit, Mich; Institute of Physiology, Czech Academy of Sciences (V.K., V.Z., M.P.), Prague, Czech Republic; and Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University (V.K., M.P.), Prague, Czech Republic.
Correspondence to Elizabeth St. Lezin, MD, Department of Laboratory Medicine, University of California, San Francisco/Mt. Zion Medical Center, 1600 Divisadero St, San Francisco, CA 94143-1613. E-mail stlezin{at}pangloss.ucsf.edu
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Abstract—Linkage studies in the fawn-hooded hypertensive rat have suggested that genes influencing susceptibility to hypertension-associated renal failure may exist on rat chromosome 1q. To investigate this possibility in a widely used model of hypertension, the spontaneously hypertensive rat (SHR), we compared susceptibility to hypertension-induced renal damage between an SHR progenitor strain and an SHR congenic strain that is genetically identical except for a defined region of chromosome 1q. Backcross breeding with selection for the markers D1Mit3 and Igf2 on chromosome 1 was used to create the congenic strain (designated SHR.BN-D1Mit3/Igf2) that carries a 22 cM segment of chromosome 1 transferred from the normotensive Brown Norway rat onto the SHR background. Systolic blood pressure (by radiotelemetry) and urine protein excretion were measured in the SHR progenitor and congenic strains before and after the induction of accelerated hypertension by administration of DOCA-salt. At the same level of DOCA-salt hypertension, the SHR.BN-D1Mit3/Igf2 congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage have been trapped in the differential chromosome segment of the SHR.BN-D1Mit3/Igf2 congenic strain. This congenic strain represents an important new model for the fine mapping of gene(s) on chromosome 1 that affect susceptibility to hypertension-induced renal injury in the rat.
Key Words: genetics • chromosome, rat, 1 • hypertension, renal
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Introduction |
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The incidence of end-stage renal disease in the United States, including the fraction attributed to hypertension, has continued to increase despite improvements in the detection and treatment of high blood pressure (BP) in the population.1 Although the link between malignant hypertension and renal failure is clear, studies have focused only recently on the extent to which mild to moderate hypertension can induce or affect the progression of renal damage.2 3 4 5 Moreover, it is unknown why just a small percentage of patients with mild to moderate hypertension develop renal failure.6 In humans, ethnic differences in the rate of hypertension-associated end-stage renal disease suggest that genetic factors might affect susceptibility to hypertension-induced renal damage.7 8 9 For example, the risk of hypertension-associated end-stage renal failure is much higher in blacks than in whites, even after correcting for severity of hypertension or differences in treatment.7 10 11 In addition, the risk of developing end-stage renal disease in siblings of blacks with hypertension-associated end-stage renal disease is far greater than that in the general population.12
In inbred animal models of hypertension, susceptibility to hypertension-induced renal damage has also been attributed to genetic factors.13 14 In genetic crosses derived from the fawn-hooded hypertensive rat (FHH), an inbred strain that develops both hypertension and renal failure, Brown et al14 mapped 2 quantitative trait loci (QTL) that influence susceptibility to renal failure to chromosome 1q. At least 1 of the QTL described (Rf-1) appears to affect the risk of renal impairment independently of an effect on BP. In contrast to the FHH, which spontaneously develops severe renal damage with relatively mild hypertension, the SHR exhibits minimal hypertensive damage, despite its having higher BPs than the FHH. In renal cross transplant studies in which susceptibility to hypertension-induced renal disease could be studied in genetically different kidneys that were simultaneously maintained in the same hemodynamic and metabolic environment, Churchill et al15 recently found that the kidney of the SHR was much less susceptible to hypertension-induced damage than the kidney of the normotensive Brown Norway rat (BN).
To investigate whether genes on chromosome 1 contribute to the difference in susceptibility to hypertension-induced renal damage between the SHR and BN strains, we compared the extent of renal damage, after we had induced accelerated hypertension, in an SHR progenitor strain and in an SHR congenic strain that carried a defined segment of chromosome 1 from BN. After the induction of a controlled degree of deoxycorticosterone acetate (DOCA)-salt–accelerated hypertension, the SHR congenic strain exhibited significantly greater renal damage than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage exist on rat chromosome 1 in the differential chromosome segment trapped in the SHR.BN-D1Mit3/Igf2 congenic strain.
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Strains
The SHR congenic strain (designated SHR.BN-D1Mit3/Igf2) was derived from a progenitor strain of SHR (SHR/Ola) as previously described.16 Briefly, the SHR congenic strain was derived by a selective breeding protocol in which a segment of chromosome 1 from the normotensive BN strain (BN/Cr) was transferred onto the genetic background of the progenitor SHR. After 10 generations of backcross breeding to the SHR progenitor strain, the SHR congenic strain was fixed using the markers D1Mit3 and Igf2, and maintained by brotherxsister mating. Previous analysis of DNA microsatellite markers showed that the SHR.BN-D1Mit3/Igf2 congenic strain is genetically identical to the progenitor SHR except for a 22 cM segment of chromosome 1 transferred from the BN/Cr strain (Figure 1).16
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Experimental Protocol
Continuous measurements of pulsatile arterial BP
were obtained in 7 male progenitor SHR and 7 male
SHR.BN-D1Mit3/Igf2 beginning at 14 to 16 weeks of age by use
of radiotelemetry transducers as previously
described.15 16 17 18 19 In brief, systolic BP (SBP)
was determined every heart beat for a 10-second interval every 10
minutes, 24 hours a day. The baseline period before DOCA-salt lasted
for 1 week, during which there were about 60 480 determinations of SBP
in each rat. After baseline BP measurements, both groups of rats were
given 100 mg/kg body weight DOCA by subcutaneous pellet and were
given a 1% NaCl/0.2% KCl solution to drink ad
libitum.15 20 DOCA-salt was administered for 33
days to increase SBP to a range of 200 to 220 mm Hg in both the
SHR progenitor and congenic strains. This protocol enabled the rapid
development of renal damage within a defined window of BP. Twenty-four
hour urine protein excretion was measured twice in each rat: first
during the final 24 hours of the 7-day baseline period, and second,
during the final 24 hours of the 33-day DOCA-salt period.
Histological Studies
After the final 24-hour urine protein collection, the kidneys
were perfusion fixed at the ambient pressure by use of 150 mmol/L
NaCl at 38°C followed by modified Karnovsky's fixative (2%
weight/volume paraformaldehyde and 2.5%
glutaraldehyde in 0.1 mol/L cacodylate buffer, pH 7.4),
as described previously.15 21 Two transverse sections of
the kidney through the papilla were postfixed in buffered formalin and
embedded in paraffin. Sections (3 to 4 µ) were stained with
hematoxylin and eosin and periodic acid Schiff. Glomerular
and vascular injury were measured separately in both of the sections
from each kidney, as previously described.15 21 All of
the glomeruli in each section were counted and classified as normal or
abnormal. Abnormal glomeruli were separated into those that exhibit (a)
acute hypertensive injury (necrosis, thrombosis, microembolisms, and
capillary wall disruption), (b) segmental glomerular
sclerosis (collapsed capillary loops with mesangial matrix
expansion), and (c) ischemic injury (globally shrunk glomeruli
with collapsed capillary loops). The percentages of glomeruli
exhibiting each of these 3 lesions were recorded. The total number
of vascular profiles exhibiting evidence of acute hypertensive injury
(fibrinoid necrosis, myointimal proliferation, fragmentation of
internal elastic lamellae, and aneurysmal dilatation) were
counted in each section. The number of such vascular profiles with
injury was expressed per 100 glomeruli as a vascular injury score to
correct for any differences in the amount of renal parenchyma
present in sections from individual kidneys.
Analysis
All results (SBP, proteinuria, and renal damage scores) are
expressed as mean±SEMs. There were 2 SBP values for each rat: (1)
baseline (the average of about 60 480 determinations during 7 days)
and (2) DOCA-salt (the average of about 285 120 determinations
during 33 days). The statistical significance of differences in mean
values between the SHR progenitor and the SHR.BN-D1Mit3/Igf2
congenic strains were analyzed by ANOVA and t tests.
A P<0.05 was considered significant.
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Results |
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Before DOCA-salt administration, SBPs and mean arterial pressures (MAPs) determined by radiotelemetry were slightly but significantly lower in the SHR.BN-D1Mit3/Igf2 congenic strain versus the SHR progenitor strain (mean SBP±SEM of SHR congenic versus progenitor rats, 161±2.2 mm Hg versus 177±2.9 mm Hg, P<0.001; MAP±SEM of SHR congenic versus progenitor rats, 146±2.4 mm Hg versus 136±1.9 mm Hg, P<0.05). However, during the period of DOCA-salt administration, the average SBPs of the congenic and progenitor rats were not significantly different and, for both strains, averaged between 200 and 220 mm Hg (Figure 2). MAPs were similarly elevated after DOCA-salt administration and showed no significant difference between progenitor and congenic strains. Although the baseline BPs of the SHR.BN-D1Mit3/Igf2 congenic rats were lower than the BPs of the SHR progenitors, no strain differences in urinary excretion of protein before administration of DOCA-salt were seen. After 33 days of DOCA-salt administration, however, proteinuria was significantly greater in the SHR.BN-D1Mit3/Igf2 congenic rats versus the progenitor SHR rats (Figure 2).
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Histologic examination of perfusion fixed kidneys demonstrated that the
SHR congenic rats carrying the chromosome 1 segment transferred from
the BN strain had significantly greater renal vascular and total
glomerular damage scores than the SHR progenitor rats,
despite exposure to the same level of DOCA-salt accelerated
hypertension (Figure 3). The kidneys of
the SHR.BN-D1Mit3/Igf2 strain showed a significantly greater
percentage of glomeruli with necrosis and ischemia (both
P<0.05) and a tendency toward greater
glomerulosclerosis (P=0.07) than did
the kidneys of the SHR progenitor rats (Figure 3). Overall,
7% of glomeruli in the SHR congenic kidneys showed histological
evidence of glomerular damage. Figure 4 illustrates the typical and contrasting
histology observed between the kidneys of the SHR progenitor rats
(Figure 4A) and the kidneys of the congenic rats (Figure 4B). Focal but severe hypertensive damage in a pattern
characteristic of malignant nephrosclerosis was
observed in the SHR.BN-D1Mit3/Igf2 kidneys. Affected vessels
showed lesions of fibrinoid necrosis, myointimal proliferation,
aneurysmal dilatation, and thrombosis. Similarly,
glomerular pathology, which is indicative of severe
hypertensive damage, was observed. The pathology included lesions of
fibrinoid necrosis and mesangiolysis, segmental sclerosis, and
ischemia. In contrast, SHR progenitor kidneys showed minimal
histological injury, despite being exposed to similar BPs.
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Discussion |
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In renal cross transplant studies between histocompatible strains of SHR and BN, Churchill et al15 demonstrated that the kidney of the BN is inherently more susceptible to hypertension-induced damage than the kidney of the SHR. The magnitude of this increase in susceptibility to hypertension-induced renal damage in BN kidneys versus SHR kidneys was
10-fold. The genes responsible for this
strain difference in susceptibility to hypertension-induced renal
damage are unknown, but previous linkage studies in the FHH suggest
that the QTL(s) that influence susceptibility to renal failure may
exist on chromosome 1q.14 In the present study, we
tested this possibility in the SHR and found that transfer of a 22 cM
segment of chromosome 1 defined by the markers D1Mit3 and
Igf2 from the BN onto the genetic background of the SHR is
sufficient to induce a significant increase in susceptibility to
hypertension-accelerated renal damage in the SHR. After elevating SBPs
in both the SHR congenic and progenitor rats to a range of 200 to
220 mm Hg by administration of DOCA-salt, the congenic SHR, which
carried the transferred segment of chromosome 1 from BN, showed
significantly greater proteinuria than the progenitor SHR. In addition,
the kidneys of congenic SHR showed an 3- to 4-fold increase in
histological evidence of both glomerular and vascular
damage versus the kidneys of progenitor SHR. Thus, our results suggest
that at least 1 gene that influences susceptibility to
hypertension-induced renal damage exists on rat chromosome 1 in the
vicinity of the markers D1Mit3 and Igf2. On
the basis of the difference in hypertension-induced renal damage found
between the SHR congenic and progenitor strains in the present
study, we estimate that gene(s) on the transferred segment of
chromosome 1 may account for 20% to 30% of the difference in
susceptibility to hypertension-induced renal damage observed between
SHR and BN kidneys in the previous crosstransplant studies.
In our initial characterization of the SHR.BN-D1Mit3/Igf2
congenic line, we found that the SBPs of male congenic SHR were 10 to
15 mm Hg lower than those of age-matched male progenitor
SHR.16 We estimated that this BP difference accounted
for 15% to 20% of the BP difference between the SHR and BN
parental strains. In the present study, we observed a similar
difference in SBP between the congenic and progenitor strains at 14 to
16 weeks of age, before administration of DOCA-salt. The increased BP
in the SHR progenitor strain versus the SHR congenic strain may allow
for protective adaptation of the SHR kidney to hypertension and promote
resistance to renal damage induced by DOCA-salt–accelerated
hypertension. However, administration of DOCA-salt for 33 days allowed
induction of a controlled, equivalent degree of accelerated
hypertension in both the SHR progenitor and congenic strains, despite
the initial 10 mm Hg difference in BP at baseline. In addition,
the previous crosstransplant experiments by Churchill et
al15 indicate that protective adaptation alone is unlikely
to explain the relative resistance to hypertension-induced renal damage
in the SHR progenitor strain. In their studies, BN kidneys were
transplanted into the histocompatible SHR.1N strain rendered
normotensive by pharmacological treatment before transplantation. After
transplantation, both the SHR.1N and BN kidneys were exposed to similar
levels of elevated BP. The kidneys transplanted from the BN rats still
showed increased renal damage versus the SHR.1N kidneys, although both
the SHR.1N and BN kidneys were exposed only to normal BPs before
transplantation.
The results of the present study are consistent with those in
the FHH in which Brown et al14 found linkage between renal
damage (as evidenced by proteinuria and renal sclerosis) and a region
of chromosome 1 defined by the markers D1Mgh12 and
D1Mit6. This locus was designated Rf-1 and mapped
45 to 60 cM away from another locus, Bpfh-1, that was
linked to an effect on BP. A second locus linked to occurrence of renal
failure, Rf-2, mapped in the vicinity of D1Mit3
17 cM away from Bpfh-1. Our present studies in the
SHR.BN-D1Mit3/Igf2 congenic strain suggest that we have
successfully isolated at least 1 gene that influences susceptibility to
hypertension-induced renal damage in the SHR model. Based on comparison
of the region of chromosome 1 transferred in our congenic
strain16 and the mapping results of Brown et
al,14 it appears that the differential chromosome segment
trapped in the SHR.BN-D1Mit3/Igf2 congenic strain overlaps
with the region containing Rf-2 and Bpfh-1 and,
possibly, with the region containing Rf-1. In linkage
studies in the stroke-prone SHR, a similar region of chromosome 1 in
the vicinity of D1Mit3 and Igf2 has been reported
to contain a gene, STR1, which influences susceptibility to
stroke.22 The current studies in the SHR, together
with previous linkage studies in the FHH and stroke-prone SHR, raise
the possibility that chromosome 1q in the rat contains QTLs that
promote susceptibility to hypertension-induced damage in a variety of
organ vascular beds.
In humans, mutations in the nephrin gene on chromosome 19q have been found to cause congenital nephrotic syndrome.23 In addition, a locus responsible for inherited focal segmental glomerulosclerosis has been linked to chromosome 19q.24 Although rat chromosome 1 is homologous to segments of human chromosomes 19q and 16p (and to mouse chromosome 7), the segment of rat chromosome 1 transferred in the SHR.BN-D1Mit3/Igf2 congenic strain does not appear to include the chromosome region implicated in human renal failure. Nevertheless, the SHR.BN-D1Mit3/Igf2 congenic strain represents a potentially important model for mapping other genes on chromosome 1 that influence susceptibility to hypertension-induced renal damage in the rat. Sublines of the SHR.BN-D1Mit3/Igf2 congenic strain are now being derived for exclusion mapping and for localizing QTL(s) with effects on BP and/or susceptibility to hypertension-induced renal damage.
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Acknowledgments |
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This work was supported by grants from the NIH to Dr Bidani (DK-40426) and to Dr Kurtz (HL-56028, HL-35018). The research of Dr Pravenec was supported in part by an International Research Scholars Award from the Howard Hughes Medical Institute, by grant 4812–3 from the ministry of Health of the Czech Republic, and by grant 204/98/K015 from the Grant Agency of the Czech Republic. Dr St. Lezin is a recipient of a Mentored Clinical Scientist Award from NIH/NHLBI and a Scientist Development Grant from the American Heart Association.
Received August 18, 1998; first decision October 20, 1998; accepted April 2, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC-VI). Arch Intern Med. 1997;157:2413–2445.
2. Brazu PC, Stead WW, Fitzwilliam, JF. Progression of renal insufficiency: role of blood pressure. Kidney Int. 1989;35:670–674.[Medline] [Order article via Infotrieve]
3. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med. 1988;318:1657–1666.[Abstract]
4. Freedman B, Iskandar S, Appel RG. The link between hypertension and nephrosclerosis. Am J Kidney Dis. 1995;25:207–221.[Medline] [Order article via Infotrieve]
5.
Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati F
L, Ford CE, Shulman NB, Stamler J. Blood pressure and end-stage renal
disease in men. N Engl J Med. 1996;334:13–18.
6.
Perneger TV, Klag MJ, Feldman HI, Whelton PK.
Projections of hypertension-related renal disease in middle-aged
residents of the United States. JAMA. 1993;269:1272–1277.
7. Rostand, SG, Brown G, Kirk KA, Rutsky AE, Dustan HP. Racial differences in the incidence and treatment for end-stage renal disease. N Engl J Med. 1982;306:1276–1279.[Medline] [Order article via Infotrieve]
8. Tierney WM, McDonald CJ, Luft FC. Renal disease in hypertensive adults: effect of race and type II diabetes mellitus. Am J Kidney Dis. 1989;13:485–493.[Medline] [Order article via Infotrieve]
9. Cusi D, Tripodi G, Casari G, Robba C, Bollini P, Merati G, Bianchi G. Genetics of renal damage in primary hypertension. Am J Kidney Dis. 1993;21(suppl 2):2–9.
10. Jones CA, Agodoa L. Kidney disease and hypertension in blacks: scope of the problem. Am J Kidney Dis. 1993;21:S6–S9.
11. McClellan W. Hypertensive end-stage renal disease in blacks: the role of end-stage renal disease surveillance. Am J Kidney Dis. 1993;21:S25–S30.
12. Freedman BI, Spray BJ, Tuttle AB, Buckalew VM. The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis. 1993;21:387–393.[Medline] [Order article via Infotrieve]
13. Weening JJ, Beukers JJB, Grond JD, Elema JD. Genetic factors in focal segmental glomerulosclerosis. Kidney Int. 1986;29:789–798.[Medline] [Order article via Infotrieve]
14. Brown DM, Provoost AP, Daly MJ, Lander ES, Jacob HJ. Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet. 1996;12:44–51.[Medline] [Order article via Infotrieve]
15. Churchill PC, Churchill MC, Bidani AK, Griffin KA, Picken M, Pravenec M, Kren V, St. Lezin E, Wang J-M, Wang N, Kurtz TW. Genetic susceptibility to hypertension-induced renal damage in the rat: evidence based on kidney specific genome transfer. J Clin Invest. 1997;100:1373–1382.[Medline] [Order article via Infotrieve]
16.
St. Lezin E, Liu W, Wang J-M, Wang N, Kren V, Krenova
D, Musilova A, Zdobinska M, Zidek V, Lau D, Pravenec M. Genetic
isolation of a chromosome 1 region affecting blood pressure in the
spontaneously hypertensive rat. Hypertension.. 1997;30:854–859.
17.
Bidani AK, Griffin KA, Picken M, Lansky DM. Continuous
telemetric blood pressure monitoring and glomerular injury
in the rat remnant kidney model. Am J Physiol. 1993;265:F391–F398.
18. St. Lezin EM, Pravenec M, Wong AL, Liu W, Wang N, Lu S, Jacob HJ, Roman RJ, Stec DE, Wang J, Reid IA, Kurtz TW. Effects of renin gene transfer on blood pressure and renin gene expression in a congenic strain of Dahl salt-resistant rats. J Clin Invest. 1996;97:522–527.[Medline] [Order article via Infotrieve]
19. St. Lezin E, Liu W, Wang N, Wang J-M, Kren V, Zidek V, Zdobinska M, Krenova D, Bottger A, van Zutphen BFM. Effect of renin gene transfer on blood pressure in the spontaneously hypertensive rat. Hypertension. 1998;31(pt 2):373–377.
20. Sesoko S, Pegram BL, Willis GW, Frohlich ED. DOCA-salt induced malignant hypertension in spontaneously hypertensive rats. J Hypertens. 1984;2:49–54.[Medline] [Order article via Infotrieve]
21.
Bidani AK, Griffin KA, Plott W, Schwartz MM. Renal
ablation acutely transforms "benign" hypertension to
"malignant" nephrosclerosis in hypertensive rats.
Hypertension. 1994;24:309–316.
22. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet. 1996;13:429–434.[Medline] [Order article via Infotrieve]
23. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan C, Peltonen L, Holmberg C, Olsen A, Tryggvason K. Positionally cloned gene for a novel glomerular protein–nephrin–is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1:575–582.[Medline] [Order article via Infotrieve]
24. Mathis BJ, Kim SH, Calabrese K, Haas M, Seidman JG, Seidman CE, Pollak MR. A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int. 1998;53:282–286.[Medline] [Order article via Infotrieve]
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