Nphs2 Gene Mutation, Atopy, And Gender As Risk Factors For Steroid-resistant Nephrotic Syndrome In Indonesians.

VOLUME 51 September‡ NUMBER 5

Original Article

NPHS2 gene mutation, atopy, and gender as risk factors

for steroid-resistant nephrotic syndrome in Indonesians

Dedi Rachmadi, Dany Hilmanto, Ponpon Idjradinata, Abdurahman Sukadi

Abstract

Background6WHURLGUHVLVWDQWQHSKURWLFV\QGURPH6516RIWHQ

GHYHORSV LQWR HQG VWDJH UHQDO GLVHDVH 3UHYLRXV VWXGLHV KDYH

reported that NPHS2JHQHPXWDWLRQJHQGHUDQGDWRSLFKLVWRU\

DUHULVNIDFWRUVDVVRFLDWHGZLWK6516,QWHUHWKQLFVRFLRFXOWXUDO DQGHQYLURQPHQWDOGLIIHUHQFHVKDYHDOVREHHQVXJJHVWHGWRDIIHFW WKHVHPXWDWLRQV

Objective 7R DQDO\]H SRVVLEOH ULVN IDFWRUV IRU 6516 LQFOXGLQJ

NPHS2 JHQH PXWDWLRQV &o7 DQG GHO* JHQGHU DQG DWRSLFKLVWRU\LQ,QGRQHVLDQVXEMHFWVZLWK6516

Methods$FDVHFRQWUROVWXG\ZLWKVXEMHFWVFRQVLVWLQJRI

6516SDWLHQWVDQGFRQWUROVXEMHFWVZDVXQGHUWDNHQLQ ,QGRQHVLDQ WHDFKLQJ FHQWUH KRVSLWDOV IURP 6HSWHPEHU WR 'HFHPEHU$QDO\VLVRIWKHNPHS2JHQHPXWDWLRQLQ &o7ZDVSHUIRUPHGE\DPSOLILFDWLRQUHIUDFWRU\PXWDWLRQV\VWHP SRO\PHUDVH FKDLQ UHDFWLRQ $5063&5 ZKLOH WKDW IRU WKH NPHS2JHQHPXWDWLRQLQGHO*ZDVSHUIRUPHGE\UHVWULFWLRQ IUDJPHQWOHQJWKSRO\PRUSKLVP5)/3'DWDZDVDQDO\]HGE\ PXOWLSOHORJLVWLFUHJUHVVLRQ

Results,QRXU,QGRQHVLDQVXEMHFWVWKHVLJQLILFDQWULVNIDFWRUV

IRU 6516 ZHUH PDOH JHQGHU 25 &, 3 NPHS2 &o7 JHQH PXWDWLRQ 25 &, 3DQGNPHS2GHO*JHQHPXWDWLRQ 25 &, 3 +RZHYHU DWRSLF KLVWRU\ZDVQRWDVLJQLILFDQWULVNIDFWRUIRU651625 &,3

Conclusion NPHS2 &o7 DQG GHO* JHQH PXWDWLRQV DVZHOODVPDOHJHQGHUDUHULVNIDFWRUVIRU6516LQ,QGRQHVLDQ VXEMHFWV$WRSLFKLVWRU\ZDVQRWVLJQLILFDQWO\DVVRFLDWHGZLWK6516 LQRXUVXEMHFWV[Paediatr Indones. 2011;51:272-6].

Keywords:Steroid-resistant nephrotic syndrome, risk factor, NPHS2 gene mutation

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Reprint requests to:'HGL5DFKPDGL0''HSDUWPHQWRI&KLOG+HDOWK )DFXOW\RI0HGLFLQH3DGMDGMDUDQ8QLYHUVLW\+DVDQ6DGLNLQ+RVSLWDO-O 3DVWHXU%DQGXQJ7HO(PDLOGHGLUDFKPDGL#

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encoding a protein that maintains the diaphragm slit

RISRGRF\WHV_{*HQHPXWDWLRQDQDO\VLVLVLPSRUWDQW}

with regards to phenotype and predicting the severity

RIFOLQLFDOPDQLIHVWDWLRQV _{The NPHS2 gene encodes}

the podocin protein and is located on chromosome

T0XWDWLRQRIWKLVJHQHKDVEHHQDVVRFLDWHG ZLWKSRRUVWHURLGUHVSRQVHLQWUHDWPHQWRIQHSKURWLF V\QGURPH 16 3UHYLRXV VWXGLHV KDYH VKRZQ WKDW

SRNS patients with an NPHS2JHQHPXWDWLRQKDG PRUH VHYHUH FOLQLFDO PDQLIHVWDWLRQV FRPSDUHG WR 6516SDWLHQWVZLWKRXWWKHNPHS2JHQHPXWDWLRQ

NPHS2JHQHPXWDWLRQVKDYHEHHQIRXQGLQ

Diversity in the NPHS2JHQHPXWDWLRQSDWWHUQ LVWKRXJKWWREHGXHWRYDULDWLRQVLQHWKQLFLW\DQG

environment. 6LQFH WKHUH ZDV QR VWXGLHV RQ

NPHS2JHQHPXWDWLRQVLQWKHSHGLDWULF,QGRQHVLDQ SRSXODWLRQZHIRFXVHGRQWKHWKLUGH[RQRINPHS2 DVDEDVLVIRUVWXG\LQ,QGRQHVLDQFKLOGUHQZLWK6516 6LQFHPDQ\IDFWRUVPD\SOD\DUROHLQWKHRFFXUUHQFH RI6516ZHLQFOXGHGJHQGHUDQGKLVWRU\RIDWRS\DV SRVVLEOHULVNIDFWRUVRI6516LQWKLVVWXG\2XUDLP ZDVWRGHWHUPLQHLINPHS2JHQHPXWDWLRQVJHQGHU DQG KLVWRU\ RI DWRS\ DUH ULVN IDFWRUV IRU 6516 LQ

Indonesian children.

Methods

$FDVHFRQWUROVWXG\ZDVFRQGXFWHGIURP6HSWHPEHU WR'HFHPEHU:HLQFOXGHGFDVHVXEMHFWV

with primary SRNS aged between 1-14 years old.

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RIWKH3DGMDGMDUDQ8QLYHUVLW\0HGLFDO6FKRRO+DVDQ 6DGLNLQ*HQHUDO+RVSLWDO%DQGXQJ

NS was diagnosed according to the International

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NS diagnoses were made by pediatric nephrologists or

SHGLDWULFLDQVVXSHUYLVHGE\SHGLDWULFQHSKURORJLVWV 'DWD DQDO\VHV ZHUH SHUIRUPHG XVLQJ 6366 YHUVLRQ 0XOWLSOH ORJLVWLF UHJUHVVLRQ DQDO\VLV ZDVXVHGWRGHWHUPLQHSRVVLEOHULVNIDFWRUVIRU6516 LQFOXGLQJ JHQH PXWDWLRQVNPHS2 &oT and

GHO*JHQGHUDQGIDPLOLDODWRSLFKLVWRU\

To detect the NPHS2 &o7 PXWDWLRQ LQ H[RQZHXVHG$5063&5_{3ULPHUGHVLJQLVVKRZQ}

inFigure 16XEMHFWV·'1$VSHFLPHQVZHUHSODFHG

LQGXSOLFDWHWXEHVRQHWXEHFRQWDLQLQJWKHZLOGW\SH DQGUHYHUVHSULPHUVDQGWKHRWKHUWXEHFRQWDLQLQJ WKHPXWDWHGDQGUHYHUVHSULPHUV6LQFHNPHS2 is an

DXWRVRPDOUHFHVVLYHJHQHDPSOLILFDWLRQVKRXOGRFFXU LQRQO\RQHWXEH

7XEHVFRQWDLQHGDPL[WXUHRIQJ'1$ SJSULPHUVX/G173PL[X0X/[ 3&5EXIIHUDQGXQLW7DTSRO\PHUDVHLQDWRWDO YRORIX/$PSOLILFDWLRQZDVSHUIRUPHGDVIROORZV GHQDWXUDWLRQDW_{&IRUWZRPLQXWHVGHQDWXUDWLRQDW &IRUVHFRQGVDQQHDOLQJDW&IRUVHFRQGV} DQGH[WHQVLRQDW_{&IRUVHFRQGVIRUF\FOHV}

Figure 1. Wild type sequence, mutated sequence and reverse primers for ARMS-PCR.

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5HYHUVHSULPHU··7*$$*$$$77**&$$*7&$*

Figure 2. Predicted PCR product, 131 base pairs.

T

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The NPHS2 GHO* DOOHOH ZDV GHWHFWHG E\ 5)/3DQDO\VLV_{7KHES3&5SURGXFWVIURPWKH} $5063&5DQDO\VLVZHUHVXEMHFWHGWR%IL,UHVWULFWLRQ HQGRQXFOHDVH7KHZLOGW\SHVHTXHQFHZLWKWKH* SUHVHQW ZDV FXW LQWR WZR IUDJPHQWV RI ES DQG ES7KHPXWDWHGVHTXHQFH*GHOHWHGUHPDLQHG XQGLJHVWHGE\%IL,5HVWULFWLRQDQDO\VLVSURGXFWVZHUH

observed by gel electrophoresis as described above.

7KH%IL,UHFRJQLWLRQVHTXHQFHORFDWHGLQWKHZLOG

type NPHS2JHQHES3&5SURGXFWLVVKRZQ

inFigure 3.

Results

$WRWDORIVXEMHFWVFRQVLVWLQJRI6516FDVHV DQG FRQWURO VXEMHFWV ZHUH HQUROOHG GXULQJ WKH VWXG\SHULRG7KHPDMRULW\ZHUHER\VLQ6516JURXS DQGLQWKHFRQWUROJURXS+LVWRU\RI DWRS\ZDVPRUHFRPPRQLQWKH6516JURXS WKDQLQWKHFRQWUROJURXS,QDGGLWLRQWKH NPHS2JHQHPXWDWLRQVZHUHPRUHFRPPRQLQWKH 6516JURXSWKDQLQWKHFRQWUROJURXS(Table 1)

0XOWLYDULDWHDQDO\VHVRIWKHSRVVLEOHULVNIDFWRUV IRU 6516 DUH GHVFULEHG LQTable 2 2I WKHVH ULVN

IDFWRUVPDOHJHQGHUDQGWKHNPHS2&oT and

GHO*JHQHPXWDWLRQVZHUHVLJQLILFDQWO\DVVRFLDWHG LQ FKLOGUHQ $FFRUGLQJ WR WKH OLWHUDWXUH PXWDWLRQ

in the NPHS2JHQHHQFRGLQJIRUSRGRFLQPD\OHDG

to SRNS.5,6,7 _{$ FDVH FRQWURO VWXG\ ZDV SHUIRUPHG} LQFKLOGUHQSUHVHQWLQJZLWK6516LQ,QGRQHVLDQ WHDFKLQJKRVSLWDOVIURP6HSWHPEHUWR'HFHPEHU

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both ArabicDQG&DXFDVLDQFKLOGUHQ4,11 _{The strong} UHODWLRQVKLS EHWZHHQ WKH RFFXUUHQFH RI 6516 DQG NPHS2 JHQH PXWDWLRQ HVSHFLDOO\ LQ H[RQ &oT, was shown by Frishberg et al. in Israeli-Arab children,DQGE\&DULGLet alLQ&DXFDVLDQFKLOGUHQ

in Italy.116LPLODUO\ZHIRXQGWKDWVXEMHFWVZLWKWKH NPHS2 &o7 JHQH PXWDWLRQ KDG WLPHV Table 1. Characteristics of subjects

Variable SNRS group N = 88

Control group N = 65 Gender, n (%)

Female Male

History of atopy, n (%) Positive

Negative

412CoT mutation, n (%) Positive

Negative

419delG mutation, n (%) Positive

Table 2. The variables as risk factors for SRNS

Variable 14 95% CI P value

Gender

412CoT mutation 419delG mutation History of atopy

2.21 < 0.001

0.003 0.262

Note: Accuracy 74.51%

Figure 3. $ſ+TGEQIPKVKQPUGSWGPEGCPFEWVRQKPVKPVJGYKNFV[RGNPHS2 _{gene. The}

419delG mutation is noted in red.

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:HDOVRFRQVLGHUHGWKHHIIHFWRIDNPHS2 gene

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method to detect all possible NPHS2JHQHPXWDWLRQ LQ H[RQ RI 6516 SDWLHQWV ZLWK IRFDO VHJPHQWDO JORPHUXORVFOHURVLV )6*64,11 _{7KH\ VXJJHVWHG WKDW} DQRWKHUNPHS2JHQHPXWDWLRQLQH[RQGHO*

was associated with SRNS in Italian children with SRNS11 _{DQG LQ D ODUJH VDPSOH VL]H RI (XURSHDQ}

children.4 _{%\ 5)/3 DQDO\VLV ZH DOVR IRXQG WKLV} PXWDWLRQWREHDVVRFLDWHGZLWK6516LQRXUVXEMHFWV

Those with the NPHS2GHO*JHQHPXWDWLRQKDG DWLPHVKLJKHUULVNIRU6516WKDQWKRVHZLWKRXW WKLVPXWDWLRQ7KLVSKHQRPHQRQPD\EHH[SODLQHG E\WKHQDWXUHRIIUDPHVKLIWPXWDWLRQVLQZKLFKWKH GHOHWLRQRIJXDQLQHDWEDVHVHTXHQFHUHVXOWVLQ IRUPDWLRQRIDGLIIHUHQWSRGRFLQSURWHLQ11

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et alREVHUYHGWKDWLQ&DXFDVLDQFKLOGUHQLQ,WDO\

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patients with an NPHS2JHQHPXWDWLRQZDV11 ,WLVGLIILFXOWWRGLIIHUHQWLDWHEHWZHHQHDUO\)6*6 DQGPLQLPDOFKDQJHQHSKURWLFV\QGURPH0&16 DV )6*6 LV FRQVLGHUHG WR EH D FRQWLQXDWLRQ RI 0&1617 _{The relationship between male gender} DQG QHSKURWLF V\QGURPH UHPDLQV XQFOHDU ,W KDV EHHQ HVWDEOLVKHG WKDW SDWKRJHQHVLV RI QHSKURWLF V\QGURPHLQYROYHV7FHOOG\VIXQFWLRQ _Abnormal

T cell clones are predominantly located in the

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boys than girls. Another theory is that SRNS with

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weight proteins. 7KH \RXQJHU DJH RI RQVHW LQ

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is needed.

The NPHS2 &o7 JHQH PXWDWLRQ OHDGV WR IRUPDWLRQ RI D WUXQFDWHG SURWHLQ 7KHNPHS2 GHO* JHQH PXWDWLRQ UHVXOWV LQ IRUPDWLRQ RI D SURWHLQ ZLWK GLIIHUHQW DPLQR DFLGV WKDQ WKDW HQFRGHGE\WKHQRUPDOJHQH+RZHYHUIXQFWLRQDO FKDQJHVRIWKHVHPXWDWHGSURWHLQVQHHGFODULILFDWLRQ ,W LV ZHOONQRZQ WKDW SKHQRW\SH DV D UHVXOW IURP WKH SUHVHQFH RI D VSHFLILF JHQH RU FRPELQDWLRQ RI JHQHVFLUFXPVWDQFHVDQGGXUDWLRQDVZHOODVWKH LQWHUDFWLRQV DPRQJ WKHVH IDFWRUV _{This theory} PD\H[SODLQWKHSKHQRW\SLFGLIIHUHQFHVLQRXUVWXG\ UHVXOWVDQGWKRVHRISUHYLRXVVWXGLHV3UHYLRXVVWXGLHV KDYH VKRZQ GLIIHUHQFHV LQ W\SH DQG IUHTXHQF\ RI NPHS2JHQHPXWDWLRQVEDVHGRQUDFLDOPDNHXS $FFRUGLQJ WR PXOWLYDULDEOH DQDO\VLV RQTable 2,

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those variables.

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to determine other possible associated NPHS2 gene

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Acknowledgments

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References

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