Genomics|HuGENet|Reviews|Tables|NPHS2, focal segmental glomerulosclerosis|PubMed ID: 16481888

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis

Franceschini, Nora MD, MPH¹; North, Kari E. PhD1; Kopp, Jeffrey B. MD²; Mckenzie, Louise PhD³; Winkler, Cheryl PhD³

Tables

Table 1: Allele frequency of non-synonymous and synonymous NPHS2 variantsa and intronic variants in normal controls by geographic area and by study population

Amino acid exchange (nucleotide position)	Country	Race or ethnicity	Control source^e	Number of individuals	Minor allele frequency proportion (95% confidence interval)	Reference
Non-synonymous changes Exon 1
P20L (59C>T)	USA	European descent	Blood donors	282	0.004 (0.00–0.009)^c	NIH^g, unpublished
	USA	African descent	Blood donors	634	Not observed	NIH, unpublished
	USA	African descent	Individuals without renal disease	96	0.005 (0.00–0.01)^b	Dusel et al., 2005¹⁸
	France	French and African descent	Control cohort	160	Not observed	Weber et al., 2004¹³
	Italy	Italians	Blood donors	260	Not observed	Caridi et al., 2003³³ and personal communication
	Germany	Central Europeans, Turkish and Indians	Healthy control subjects	80	0.025 (0.00–0.05)^d	Ruf et al., 2004³⁵
G34E (101G>A)	Japan	Japanese	Unrelated healthy volunteers	44	0.02 (0.00 to 0.05)^d	Maruyama et al., 2003¹⁶
G42R	USA	European descent	Blood donors	281	Not observed	NIH, unpublished data
	USA	African descent	Blood donors	634	0.014 (0.01 to 0.02)^c	NIH, unpublished data
A44E (176C>A)	USA	African descent	Individuals without renal disease	96	0.005 (0.00 to 0.01)^b	Dusel et al., 2005¹⁸
	USA	African descent	Individuals without renal disease	96	0.016 (0.00 to 0.03)^b	Dusel et al., 2005¹⁸
	France	French and African descent	Control cohort	160	Not observed	Weber et al.¹³
Exon 3
R138Q (413G>A)	USA	European descent	Blood donors	272	0.002 (0.00 to 0.005)^c	NIH, unpublished data
	USA	African descent	Blood donors	75	0.002 (0.00 to 0.009)^c	NIH, unpublished data
	Germany	Northern Europeans	Healthy controls	100	Not observed	Karle et al., 2002²¹
Exon 5
R229Q (686G>A)	USA	Africans and African descent	Controls	32	0.016 (0.01 to 0.05)^b	Tsukaguchi et al., 2002³
	Brazil	Not reported	Controls from Brazil	49	0.031 (0.00 to 0.07)^b	Tsukaguchi et al., 2002³
	USA/West Europe	Majority European	Individuals without kidney disease (spouses of FSGS patients)	124	0.036 (0.01 to 0.06)^b	Tsukaguchi et al., 2002³
	USA	African descent	Blood donors, IV drugs abusers from the ALIVE cohort^h	634	0.013 (0.007 to 0.02)^c	NIH, unpublished data
	USA	European descent	Blood donors and healthy volunteers	272	0.039 (0.02 to 0.06)^c	NIH, unpublished data
	USA	African descent	Individuals without renal disease	96	0.005 (0.00 to 0.01)^b	Dusel et al., 2005¹⁸
	Brazil	African descent	Participants of the WHO- MONICA cohort study^f	NR	0.025^b	Pereira et al, 2004¹⁷
	Brazil	Mulatto		NR	0.049^b	Pereira et al, 2004¹⁷
	Brazil	European descent		NR	0.069^b	Pereira et al, 2004¹⁷
	Brazil	All races		1755	0.0276 (0.02 to 0.03)^c	Pereira et al, 2004¹⁷
	Germany	Germans	Healthy controls	100	0.03 (0.006 to 0.05)^c	Karle et al., 2002²¹
	Germany	Central Europeans, Turkish and Indians	Healthy control individuals	80	0.056 (0.02 to 0.09)^b	Ruf et al., 2004³⁵
	France	French and African descent	Control cohort	160	0.038 (0.02 to 0.06)^c	Weber et al., 2004¹³
	Italy	Italians	Blood donors	260	0.02 (0.008 to 0.03)^c	Caridi et al., 2003³³ and personal communication
	Italy	Italians	Blood donors	124	0.028 (0.007 to 0.05)^c	Aucella et al., 2005³⁴
	Sweden	Europeans, Asians, Maltese	Normal controls	60	Not observed	Koziell et al., 2002¹²
E237Q (709G>C)	USA	Europeans descent	Individuals without renal disease	96	Not observed	Dusel et al., 2005¹⁸
	France	French and African descent	Control cohort	160	0.003 (0.00 to 0.009)^c	Weber et al., 2004¹³
A242V (725C>T)	USA	Europeans descent	Blood donors	282	0.002 (0.00 to 0.006)	NIH, unpublished data
	USA	African descent	Blood donors	603	0.062 (0.05 to 0.08)^c	NIH, unpublished data
	USA	African descent	Individuals without renal disease	278	0.087 (0.06 to 0.11)^b	Dusel et al., 2005¹⁸
	France	French and African descent	Control cohort	160	0.006 (0.00 to 0.01)^c	Weber et al., 2004¹³
	France	African descent	Control cohort	75	0.04 (0.008 to 0.07)^c	Weber et al., 2004¹³
Synonymous changes
Exon 1
G34G (102G>A)	USA	African descent	Individuals without renal disease	96	0.15 (0.10 to 0.20)^b	Dusel et al., 2005¹⁸
	Germany	Europeans	Healthy controls	100	Not reported^b	Karle et al., 2002²¹
Exon 2
S96S (288C>T)	USA	African descent	Individuals without renal disease	96	0.098 (0.06 to 0.14)^b	Dusel et al., 2005¹⁸
	China	Han Chinese	Healthy controls	50	0.06 (0.01 to 0.11)^c	Wu et al., 2001¹⁹
	China	Chinese	Unrelated volunteers	53	0.04 (0.003 to 0.08)^c	Yu et al., 2005³⁹
	Italy	Europeans	Blood donors	50-70	0.06^c	Caridi et al., 2001²²
Exon 7
A297A	USA	African descent	Individuals without renal disease	96	0.016 (0.00 to 0.03)^b	Dusel et al., 2005¹⁸
Exon 8
A317A (951T>C)	Italy	Europeans	Blood donors	50-70	0.42^c	Caridi et al., 2001²²
A318A (954T>C)	USA	African descent	Individuals without renal disease	278	0.40 (0.36 to 0.44)^b	Dusel et al., 2005¹⁸
	China	Han Chinese	Healthy controls	50	0.51 (0.44 to 0.58)^d	Wu et al., 2001²⁰
	Japan	Japanese	Unrelated healthy volunteers	44	0.43 (0.33 to 0.53)^c	Maruyama et al., 2003¹⁶
	China	Chinese	Unrelated volunteers	53	0.42 (0.33 to 0.51)^c	Yu et al., 2005³⁹
	Germany	Europeans	Healthy controls	100	Not reported	Karle et al., 2002²¹
L346L (1038A>G)	USA	African descent	Individuals without renal disease	96	0.095 (0.05 to 0.14)^b	Dusel et al., 2005¹⁸
	China	Han Chinese	Healthy controls	50	0.06 (0.01 to 0.11)^c	Wu et al., 2001²⁰
	Japan	Japanese	Unrelated healthy volunteers	44	0.00 (0.00 to 0.00)^c	Maruyama et al., 2003¹⁶
	China	Chinese	Unrelated volunteers	53	0.04 (0.003 to 0.08)^c	Yu et al., 2005³⁹
	Italy	Italians/Europeans	Blood donors	50-70	0.03^c	Caridi et al., 2001²²
A1023G/	Israel	Arab-descent	Healthy unrelated individuals	40	Unable to calculate from study	Frishberg et al., 2002⁴⁰
	Israel	Jewish-descent	Healthy unrelated individuals	40		Frishberg et al., 2002⁴⁰
Untranslated regions# Promoter
-2169A>T	USA	African descent	Individuals without renal disease	96	0.021 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-1842C>G	USA	African descent	Individuals without renal disease	96	0.026 (0.00 to 0.05)^b	Dusel et al., 2005¹⁸
-1709G>A	USA	African descent	Individuals without renal disease	96	0.108 (0.06 to 0.15)^b	Dusel et al., 2005¹⁸
-1707delCT	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
-1628G>C	USA	African descent	Individuals without renal disease	96	0.069 (0.03 to 0.10)^b	Dusel et al., 2005¹⁸
-1441G>A	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
-1376G>A	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
-1147delATCT	USA	African descent	Individuals without renal disease	96	0.021 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-999T>A	USA	African descent	Individuals without renal disease	96	0.148 (0.10 to 0.20)^b	Dusel et al., 2005¹⁸
-748C>T	USA	African descent	Individuals without renal disease	96	0.088 (0.05 to 0.13)^b	Dusel et al., 2005¹⁸
-704G>A	USA	African descent	Individuals without renal disease	96	0.019 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-670C>T	USA	African descent	Individuals without renal disease	96	0.236 (0.18 to 0.30)^b	Dusel et al., 2005¹⁸
-556delCTTTTTT	USA	African descent	Individuals without renal disease	96	0.135 (0.09 to 0.18)^b	Dusel et al., 2005¹⁸
-494G>A	USA	African descent	Individuals without renal disease	96	0.019 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-486insA	USA	African descent	Individuals without renal disease	96	0.156 (0.10 to 0.21)^b	Dusel et al., 2005¹⁸
-440T>C	USA	African descent	Individuals without renal disease	96	0.019 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-364C>T	USA	African descent	Individuals without renal disease	96	0.021 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
-185T>C	USA	African descent	Individuals without renal disease	96	0.085 (0.05 to 0.12)^b	Dusel et al., 2005¹⁸
-116C>T	USA	African descent	Individuals without renal disease	96	0.109 (0.06 to 0.15)^b	Dusel et al., 2005¹⁸
5' untranslated region
-51G>T	China	Chinese	Unrelated volunteers	53	0.15 (0.08 to 0.22)^c	Yu et al., 2005³⁹
	USA	African descent	Individuals without renal disease	96	0.179 (0.12 to 0.23)^b	Dusel et al., 2005¹⁸
-52C>G	USA	African descent	ndividuals without renal disease	96	0.168 (0.12 to 0.22)^b	Dusel et al., 2005¹⁸
Intron 1
Sequence:	Italy	Italians	Blood donors	50-70	5 alleles	Caridi et al., 2001²²
CACGCATGTTT					1=0.01
ATAGCAGCACT					2=0.29
CCTCTTCATGG					3=0.27
CTGAGTAGC					4=0.34
(301 to 309)					5=0.09
Intron 3
IVS3-46C>T	China	Chinese	Unrelated volunteers	53	0.06 (0.01 to 0.11)^c	Yu et al., 2005³⁹
	USA	African descent	Individuals without renal disease	96	0.06 (0.03 to 0.09)^b	Dusel et al., 2005¹⁸
IVS3-21C>T	China	Chinese	Unrelated volunteers	53	0.06 (0.01 to 0.11)^c	Yu et al., 2005³⁹
	USA	African descent	Individuals without renal disease	96	0.06 (0.03 to 0.09)^b	Dusel et al., 2005¹⁸
IVS3+9insA	USA	African descent	Individuals without renal disease	278	0.002 (0.00 to 0.006)^c	Dusel et al., 2005¹⁸
IVS3-144C>T	USA	African descent	Individuals without renal disease	96	0.033 (0.01 to 0.06)^b	Dusel et al., 2005¹⁸
IVS3-31T>C	USA	African descent	Individuals without renal disease	96	0.136 (0.09 to 0.18)^b	Dusel et al., 2005¹⁸
Intron 4
IVS4-98C>T	USA	African descent	Individuals without renal disease	96	0.021 (0.00 to 0.04)^b	Dusel et al., 2005¹⁸
Intron 5
IVS5+110T>A	USA	African descent	Individuals without renal disease	96	0.163 (0.11 to 0.22)^b	Dusel et al., 2005¹⁸
Intron 7
EX7+7A>G	Italy	Italians	Blood donors	50-70	0.04^c	Caridi et al., 2001²²
IVS7+7A>G	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
IVS7+132A>G	USA	African descent	Individuals without renal disease	96	0.016 (0.00 to 0.03)^b	Dusel et al., 2005¹⁸
IVS7+261C>T	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
IVS7+304T>C	USA	African descent	Individuals without renal disease	96	0.01 (0.00 to 0.02)^b	Dusel et al., 2005¹⁸
IVS7-74G>C	China	Chinese	Unrelated volunteers	53	0.04 (0.003 to 0.08)^c	Yu et al., 2005³⁹
	USA	African descent	Individuals without renal disease	96	0.095 (0.05 to 0.14)^b	Dusel et al., 2005¹⁸
3' untranslated region
1206C>G	USA	African descent	Individuals without renal disease	96	0.40 (0.36 to 0.44)^b	Dusel et al., 2005¹⁸
1309A>G	USA	African descent	Individuals without renal disease	96	0.116 (0.07 to 0.16)^b	Dusel et al., 2005¹⁸
1352G>A	USA	African descent	Individuals without renal disease	96	0.058 (0.02 to 0.09)^b	Dusel et al., 2005¹⁸
1410A>G	USA	African descent	Individuals without renal disease	96	0.20 (0.17 to 0.23)^b	Dusel et al., 2005¹⁸
1580G>A	USA	African descent	Individuals without renal disease	96	0.144 (0.09 to 0.19)^b	Dusel et al., 2005¹⁸
1589G>T	USA	African descent	Individuals without renal disease	96	0.013 (0.00 to 0.03)^b	Dusel et al., 2005¹⁸

^aA polymorphism was defined as an allele frequency equal or greater than 1% in at least one studied population.
^bReports Hardy Weinberg Equilibrium (HWE) but genotype frequency distribution not published.
^cCan not reject null hypothesis of HWE based on published genotype frequency distribution, P = 0.27– 0.96.
^dReject null hypothesis of HWE, P < 0.001 for P20L, P = 0.002 for G34E and P= 0.02 for A318A.
^eControls were ethnic matched unless stated otherwise.
^fWorld Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease, a cross-sectional study of risk factors for cardiovascular disease performed in Vitoria, Brazil.
^gNIH, National Institutes of Health.
^hALIVE, AIDS Link to Intravenous Experience cohort study, Baltimore, MD.

Table 2: Genotype frequencies for R229Q polymorphism in NPHS2 by geographic area and by study population

Country	Race/ethnicity	Study sample	Genotype frequency			HWE^b P-value	Frequency of heterozygotes	Reference
Country	Race/ethnicity	Study sample	GG	AG	AA	HWE^b P-value	Frequency of heterozygotes	Reference
USA	African descent	634	318	16	0	0.65	0.03	NIH^a, unpublished
USA	European descent	272	251	21	0	0.36	0.07	NIH, unpublished
USA	Western individuals	124	115	9	0	0.67	0.07	Tsukaguchi et al., 2002³
Brazil	European, African descent and mixed	1577	1491	85	1	0.99	0.05	Pereira et al., 2004¹⁷
Germany	Central Europeans, Turkish and Indians	80	71	9	0	0.18	0.13	Ruf et al., 2004³⁵
Germany	Europeans	100	94	6	0	0.76	0.06	Karle et al., 2002²¹
France	French/African descent	160	148	12	0	0.62	0.08	Weber et al., 2004¹³
Italy	Italian Caucasians	260	252	8	0	0.80	0.03	Caridi et al., 2003³³ and personal communication
Italy	Italian Caucasians	124	117	7	0	0.75	0.05	Aucella et al., 2005³⁴

^a NIH, National Institutes of Health.
^bHWE, Hardy-Weinberg Equilibrium.

Table 3: Findings from studies of the relation between NPHS2 polymorphism R229Q (686G/A) and nephrotic syndrome or focal segmental glomerulosclerosis

Country/ethnicity		Phenotype	Cases		Controls		Crude odds ratio		References
Country/ethnicity		Phenotype	G/G n	G/A n	G/G n	G/A n	Disease	ORa (95% CI)	References
Europe
	Germany/mostly Germans, other Europeans	SRNS^b; median age 3 years (range 0.1 to 16.6 years)	25	0	94	6	SRNS	Unable to calculate	Karle et al., 2002²¹
	Italy/Caucasian Italians	SRNS and SSNS^b; age of 70 months (range 1 to 216); 71% were FSGS	113 54	7 5	95	5	SRNS SSNS Combined	1.2 (0.4 to 3.8) 1.8 (0.5 to 6.4) 1.4 (0.5 to 4.0)	Caridi et al., 2003³³
	France/Europe (mainly France) and North Africa	SRNS; mean age was 103 months; 66% were FSG	158^d	11	148	12	SRNS	0.9 (0.4 to 2.0)	Weber et al., 2004¹³
	Germany/ Central Europeans, Turkish and Indians	SRNS from 165 families (median age 3.5 years); SSNS from 120 families (median age 4.4 years)	177 118	13^e6^e	71	9	SRNS SSNS	c	Ruf et al., 2004³⁵
	Italy/ Italians	Adult-onset FSGS^b, mean age 36 years (range 12–57)	30	3	117	7	FSGS	1.7 (0.8 to 6.9)	Aucella et al., 2005³⁴
United States of America
	USA/Northeast US	Adults with FSGS (63 Caucasians, 17 African American, 11 Hispanics)	80	911^g	115	9^h	FSGS FSGS^g	1.4 (0.5 to 3.8)^f 1.8 (0.7 to 4.4)^f	Tsukaguchi et al., 2002³
	USA	Adult FSGS African descent	243	5	618	16	FSGS	0.8 (0.3 to 2.2)	NIH, unpublished
	USA	Adult FSGS European descent	118	12	251	21	FSGS	1.2 (0.6 to 2.5)	NIH, unpublished

^aOR, odds ratio; CI, confidence interval. Estimates were calculated using published data.
^bSRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; FSGS, focal segmental glomerulosclerosis.
^cUnable to calculate due to unknown frequency of heterozygous by family.
^dTwo individuals with A/A alleles and one compound heterozygote were excluded from the case strata.
^eCombined homozygous, heterozygous or compound heterozygous individuals.
^fResults may be confounded by population admixture.
^gTwo of 11 were compound heterozygous.
^hControls from the Western panel of DNA samples.