線粒體相關(guān)腎病2例病例報告及文獻復(fù)習(xí)

李國民 孫 利 沈 茜 徐 虹 方曉燕 曹 琦 劉海梅 翟亦暉 吳冰冰劉學(xué)光 楊 青

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·論著·

線粒體相關(guān)腎病2例病例報告及文獻復(fù)習(xí)

李國民1, 5孫 利1,5沈 茜1徐 虹1方曉燕1曹 琦1劉海梅1翟亦暉1吳冰冰2劉學(xué)光3楊 青4

目的 總結(jié)2例線粒體相關(guān)腎病患兒臨床特征及基因突變的特點，提高對該病的認識。方法 收集2例線粒體相關(guān)腎病患兒的病史特點、腎臟病理、相關(guān)實驗室檢查和家族史等資料。采用外顯子捕獲的方法對4 000種人類單基因病的相關(guān)致病基因進行高通量測序，包括線粒體DNA A3243G等37個基因和ADCK4等13個參與輔酶Q10生物合成的基因，利用生物信息學(xué)對測序結(jié)果進行分析，用Sanger法對高通量測序結(jié)果進行驗證，并在家系中進行突變分析。并進行相關(guān)文獻復(fù)習(xí)。結(jié)果 2例患兒男女各1例。女性患兒11.7歲起病，主要臨床表現(xiàn)為蛋白尿和腎功能異常，無腎外癥狀，腎臟病理為局灶節(jié)段性腎小球硬化(FSGS)，檢測到NPHS1基因已報道的p.E447K和p.G601A雜合突變，ADCK4基因純合p.D209H錯義突變，為新發(fā)現(xiàn)的突變。家系突變分析發(fā)現(xiàn)，NPHS1基因p.E447K和p.G601A雜合突變均來自父親，其哥哥也有相同的基因型，其母親不攜帶該2個突變；患兒父母和哥哥分別攜帶p.D209H雜合突變。男性患兒出生后起病，多個系統(tǒng)受累，表現(xiàn)為精神、運動發(fā)育落后，心臟和大血管多發(fā)畸形，腎病綜合征。檢測到COQ6基因的純合p.R360W錯義突變，為新發(fā)現(xiàn)的突變。家系突變分析顯示，患兒父母分別攜帶雜合p.R360W錯義突變。ADCK4基因p.D209H錯義突變和COQ6基因p.R360W錯義突變經(jīng)在線軟件PolyPhen和SIFT預(yù)測為有害性突變，經(jīng)多物種蛋白序列比對，2個突變位點均具有保守性。結(jié)論 2例患兒腎臟表型分別由輔酶Q10合成基因ADCK4和COQ6突變引起的線粒體相關(guān)腎病。新發(fā)現(xiàn)p.D209H和p.R360W突變分別豐富了ADCK4和COQ6基因突變譜。

線粒體?。?蛋白尿； 腎病綜合征；COQ6基因；ADCK4基因

1 病例報告

例1，女，14歲。2014年5月7日因“發(fā)現(xiàn)蛋白尿1月余”就診于復(fù)旦大學(xué)附屬兒科醫(yī)院(我院)，以蛋白尿原因待查收入我院。

患兒1個月前因“白頭發(fā)增多”就診當(dāng)?shù)蒯t(yī)院，查尿常規(guī)蛋白3+，未見全身水腫，無尿頻、尿急和尿痛，無肉眼血尿及少尿，SCr 98.1 μmol·L-1， BUN 6.1 mmol·L-1，內(nèi)生肌酐清除率74 mL·min-1·s-2，腎臟病理學(xué)檢查提示“早期硬化腎小球腎炎”，予黃葵膠囊和貝那普利口服，尿蛋白仍3+。

患兒系G2P2，足月順產(chǎn)，出生體重3 400 g，既往體健，否認食物、藥物過敏史。患兒父母體健，非近親婚配，母親妊娠史2-0-0-2，患兒有一個哥哥，體健。

入院查體：血壓110/70 mmHg，身高152.0 cm(P50)，體重44.0 kg(P50)，神志清楚，精神可。全身未見水腫。心、肺、腹部和神經(jīng)系統(tǒng)查體未見異常。

實驗室檢查：尿沉渣：蛋白2+、RBC 0.41·HP-1、WBC 0.29·HP-1；尿蛋白/CR 2.79，尿鈣/CR 0.04，24 h尿蛋白2.87 g。尿微量蛋白A1M 6.12 mg·L-1，A1MU/CR 22.0 mg·g-1，ALBU 741.0 mg·L-1，ALBU/CR 2 667 mg·g-1，IGGU 22.7 mg·L-1，IGGU/CR 81.7 mg·g-1，NAG 5.2 U·L-1，NAG/CR 2.12 U·mol-1，尿轉(zhuǎn)鐵蛋白31.9 mg·L-1。血常規(guī)、肝功能、血電解質(zhì)、血脂、免疫球蛋白和補體指標(biāo)均正常。自身抗體陰性。SCr 74.0 μmol·L-1，BUN 6.6 mmol·L-1，尿酸44 μmol·L-1，甲狀旁腺素182 pg·mL-1。血氣分析：pH 7.270、BE -4.2 mmol·L-1。

調(diào)閱患兒外院的腎活檢病理切片，我院行重新閱片：光鏡12個腎小球，7個球性硬化，1個局灶節(jié)段性腎小球硬化，4個腎小球正常，明顯腎小管萎縮及間質(zhì)纖維化，腎血管無異常(圖1A～C)；電鏡下足細胞足突部分融合(圖1D)；免疫熒光顯微鏡顯示(圖1E～H)：系膜區(qū)有IgM、IgA、IgG、C1q和C3沉積(+～++)。 DTPA示雙腎灌注欠佳，功能受損，排泄延遲，雙腎腎小球濾過率(GFR，未標(biāo)化)48.4 mL·min-1(左腎26.5、右腎21.9)，腎臟MR示左腎實質(zhì)多發(fā)性異常信號，髓質(zhì)海綿腎待排除，右腎偏小伴右腎可疑異常信號。腎臟磁共振水成像(MRU)和膀胱逆行造影(MCU)未見異常。

診斷：局灶節(jié)段性腎小球硬化(FSGS)、慢性腎臟病2期。

因家長拒絕糖皮質(zhì)激素治療，繼續(xù)予貝那普利和和黃葵膠囊口服治療。

例2，男，10月齡。2015年4月因“心臟雜音，肌張力低下”就診并收入我院。

患兒出生后因“嘔吐14 h”入住當(dāng)?shù)蒯t(yī)院，診斷“新生兒不全性腸梗阻、敗血癥、先天性心臟病、新生兒肺炎、新生兒窒息、新生兒腦病、肝功能異常、鞘膜積液和足月小樣兒”，經(jīng)治療好轉(zhuǎn)出院(具體治療不詳)。1個月前因“右側(cè)腹股溝復(fù)發(fā)性包塊8個月”再就診當(dāng)?shù)蒯t(yī)院，查體發(fā)現(xiàn)生長發(fā)育落后、左眼瞼下垂和四肢肌張力低下；頭顱MRI示雙側(cè)大腦萎縮，行右側(cè)腹股溝嵌頓性斜疝復(fù)位和疝囊高位結(jié)扎術(shù)?；純阂蚓?、運動發(fā)育落后來我院就診，心臟超聲示：肺動脈狹窄、動脈導(dǎo)管未閉、房間隔缺損、降主動脈流速增快、永存左上腔靜脈。

患兒系G1P1，足月順產(chǎn)，出生體重1 700 g，血性羊水，輕度窒息。生長發(fā)育遲緩，目前不能抬頭、不能坐；父母親體健，非近親婚配，母親妊娠史1-0-0-1，家族成員否認遺傳性疾病史。

入院查體：血壓88/50 mmHg，身高65.0 cm(P25)，體重5.0 kg (P25)，神志清楚，精神、反應(yīng)欠佳，左側(cè)上眼瞼下垂，全身未見明顯水腫。HR 130·min-1，律齊，心前區(qū)可聞及收縮期Ⅲ/6雜音，以胸骨左緣第2、3肋間最為明顯；腹軟，無壓痛及反跳痛；四肢肌張力低下，不能豎頭，不能坐立，克氏、布氏征均陰性。

輔助檢查： 尿沉渣：蛋白3+、RBC 0～1·HP-1，WBC 2～3·HP-1；24 h尿蛋白1.04 g ；血常規(guī)：Hb 85 g·L-1，RBC 2.64×1012·L-1；血生化：ALT 24 U·L-1，AST 43 U·L-1，總蛋白44.8 g·L-1，白蛋白22.5 g·L-1，總膽固醇5.43 mmol·L-1，三酰甘油2.38 mmol·L-1，SCr 14.0 μmol·L-1，BUN 4.2 mmol·L-1，尿酸218.0 μmol·L-1。血電解質(zhì)正常。TORCH抗體均陰性，梅毒、HIV和乙肝血清學(xué)檢查均陰性。免疫球蛋白和補體均正常。血氣分析：pH 7.496，BE -0.5 mmol·L-1。泌尿系統(tǒng)B超檢查未有異常發(fā)現(xiàn)。

診斷：先天性心臟病，腎病綜合征，先天性腦發(fā)育不良、左側(cè)上眼瞼下垂。

行心導(dǎo)管造影和經(jīng)皮動脈導(dǎo)管未閉封堵術(shù),術(shù)后予阿司匹林、呋塞米和螺內(nèi)酯口服。

圖1 例1腎組織病理學(xué)檢查

Fig 1 Histological changes of kidney in case 1

Notes A-C displayed several sclerosis glomeruli by HE, PAS and PASM staining under light microscope (×200); D showed some fusion of foot processes by electron microscope (×7 000); E-H showed IgG, IgM, C1q and C3 deposition (×200) under immunofluorescence microscope, respectively

2 測序分析

2.1 高通量測序 使用Hiseq 2500高通量模式行PE100測序，按Hiseq 2500標(biāo)準(zhǔn)流程進行。通過Q30的標(biāo)準(zhǔn)對原始數(shù)據(jù)進行數(shù)據(jù)過濾得到cleandata和高質(zhì)量的測序結(jié)果。使用bwa比對軟件，使用samtool和pindel分析軟件得到最初的raw突變；然后經(jīng)過重復(fù)區(qū)域、ssr、突變質(zhì)量值、突變深度、突變率等嚴格過濾，得到高度可靠的突變，在dbSNP，OMIM，uniprot，ClinVar等數(shù)據(jù)庫中進行檢索和過濾，得到各個突變的疾病關(guān)聯(lián)信息。

2.2 直接測序(Sanger法)驗證 首先對高通量測序所檢測到的可疑致病基因及突變位點行生物信息學(xué)分析(參照文獻[1])，確定突變的性質(zhì)；其次對致病性突變進行遺傳學(xué)分析，并與患兒的臨床表型比較，選擇臨床表型較吻合的突變基因及其致病性突變位點進行驗證。本文患兒發(fā)現(xiàn)的突變位點，首先利用Sanger直接測序的方法在患兒父母中進行突變位點驗證。對新發(fā)現(xiàn)的錯義突變進行在線 PolyPhen和SFIT預(yù)測，并通過多物種蛋白序列比對分析新突變位點的保守性。

2.3 篩選流程 見圖2。

2.4 測序結(jié)果 4 000種單基因高通量測序和Sanger法驗證發(fā)現(xiàn)，例1存在NPHS1基因已報道的p.E447K和p.G601A雜合突變，ADCK4基因純合p.D209H錯義突變，為新發(fā)現(xiàn)的突變。家系突變分析發(fā)現(xiàn)，NPHS1基因p.E447K和p.G601A雜合突變均來自父親，其哥哥也有相同的基因型，其母親不攜帶突變(圖3A)；患兒父母和哥哥分別攜帶雜合p.D209H錯義突變(圖3A)。例2檢出COQ6基因的純合p.R360W錯義突變 ， 為新發(fā)現(xiàn)的突變。

圖2 篩選流程圖

Fig 2 Filter flow chart

Notes 1)北京德易東方醫(yī)學(xué)轉(zhuǎn)化中心數(shù)據(jù)庫

家系突變分析顯示，患兒父母分別攜帶雜合p.R360W錯義突變(圖3B)。2例患兒均確診為線粒體相關(guān)腎病。

2.5 測序結(jié)果分析ADCK4基因p.D209H突變和COQ6基因的p.R360W突變均為錯義突變，經(jīng)在線軟件PolyPhen 和SIFT預(yù)測為有害性突變。多物種蛋白序列比對發(fā)現(xiàn)，突變位點具有保守性。

圖3 例1和2高通量測序結(jié)果

Fig 2 Results of high-flux sequencing in cases 1 and 2

Notes A: mutational analysis inNPHS1 andADCK4 gene in family of patent 1；B: mutational analysis inCOQ6 gene in family of patent 2; P: patient, F: father, M: mother, S: sibling

3 治療和隨訪

例1和2基因確診后均予輔酶Q10 15～30 mg·kg-1·d-1口服，例1隨訪6個月，尿蛋白+～2+，SCr 80～123 μmol·L-1，BUN 6.0～7.0 mmol·L-1。例2隨訪6個月，尿蛋白3+～4+，SCr 19～23μmo·L-1，BUN 3.6～4.0 mmol·L-1，臨床癥狀加重不明顯。

4 討論

4.1 線粒體基因和核基因突變所致腎病文獻復(fù)習(xí) 線粒體病是最常見和最復(fù)雜的遺傳性疾病，其遺傳方式涉及到線粒體基因(mtDNA)的母系遺傳和核基因(nDNA)的孟德爾遺傳[2]。各種遺傳缺陷導(dǎo)致的線粒體結(jié)構(gòu)和功能異?？梢l(fā)多個系統(tǒng)能量代謝障礙，常累及腦、骨骼肌、眼、耳、消化、內(nèi)分泌、心血管及血液系統(tǒng)等[3]。近年來研究發(fā)現(xiàn)，多種線粒體基因或核基因遺傳缺陷引起的線粒體功能障礙還可累及腎臟(表1,2[4～24]和3[25～44])，稱為線粒體相關(guān)腎病，臨床上對該病常認識不足。線粒體相關(guān)腎病可表現(xiàn)為腎小管功能障礙、間質(zhì)性腎炎、囊性腎病變以及腎小球性病變。線粒體基因和線粒體蛋白編碼的核基因突變均可引起腎小球病變，表現(xiàn)為蛋白尿或腎病綜合征，既可伴有腎外癥狀，也可僅表現(xiàn)為腎小球受累，腎臟病理多為FSGS[4,7,16,25～27,29,45～47]，對激素治療及免疫抑制劑治療無效，其中影響輔酶Q10合成基因突變的一部分患者對輔酶Q10治療有效[29,48～51]。目前線粒體相關(guān)腎病在國內(nèi)尚未見報道，國外報道也罕見。

表1 文獻報道的線粒體基因點突變相關(guān)腎病

Notes 1) Single noncoding base between mt-tRNAAlaand mt-tRNAAsn. mt-tRNA: mitochondrial transfer ribonucleic acid; TIN: tubulointerstitial nephritis; FSGS: focal segmental glomerulosclerosis; RTA, renal tubular acidosis; Phe: phenylalanine; Leu: leucine; Ile: isoleucine; Tyr: tyrosine; Ala: alanine; ND5: NADH dehydrogenase 5

4.2線粒體相關(guān)腎病臨床表型文獻復(fù)習(xí)本文例1起病年齡為11.7歲，表現(xiàn)為蛋白尿和腎功能受損，無腎外癥狀，腎臟病理為FSGS。高通量測序和Sanger法驗證檢出NPHS1基因p.E447K和p.G601A雜合突變，為已報道的致病性突變[52,53]，但家系分析發(fā)現(xiàn)該2個突變均來自父親，患兒哥哥也有相同基因型，其母親不攜帶這2個突變；因患兒父親和哥哥均無蛋白尿等表現(xiàn)，推測該2個突變位于相同的等位基因上。例1還檢出ADCK4基因p.D209H純合突變，其父母和同胞分別攜帶p.D209H雜合突變，經(jīng)在線軟件分析為有害性突變，其突變位點具有保守性，提示該位點應(yīng)為致病性突變，且為新發(fā)現(xiàn)的突變。國外1項研究匯總8個家庭15例ADCK4基因突變患兒，均表現(xiàn)激素耐藥腎病綜合征，13例有腎活檢資料，其中1例為球性硬化，12例為FSGS(包括3例塌陷性FSGS)，臨床資料完整的9例患兒中，1例有甲狀腺腫伴高血壓，1例智力發(fā)育延遲，1例擴張性心肌病(表4)[29,54]。另一項研究報道了12個家庭26例青少年期起病的患兒，平均發(fā)病年齡14.1(10.8～17.0)歲，其中61.5%患兒行腎活檢，腎病病理均為FSGS，43.9%有腎病范圍蛋白尿，46.1%病例確診時為慢性腎臟病3～5期，3例偶有驚厥發(fā)作，1例智力落后，1例色素性葡萄膜炎[30]。本文患兒僅表現(xiàn)為非腎病水平蛋白尿，尿微量蛋白提示以白蛋白增高為主，腎功能異常，不伴有腎外表型，其臨床特點與上述2項研究報道的病例相似，可診斷為線粒體相關(guān)腎病，即ADCK4基因相關(guān)腎小球疾病。該病可無腎外癥狀，腎臟表現(xiàn)可以為激素耐藥腎病綜合征(腎病水平蛋白尿)，也可為非腎病水平蛋白尿，易進展為終末期腎病。

表2 文獻報道的線粒體基因缺失相關(guān)腎病

Notes TIN: tubulointerstitial nephritis; FSGS: focal segmental glomerulosclerosis; RTA, renal tubular acidosis; PT: proximal tubulopathy

表3 線粒體蛋白編碼的核基因相關(guān)腎病

Tab 3 Nuclear genes encoding mitochondrial proteins associated nephropathy

GeneChromosomepositionRenalphenotypeRef.CoenzymeQ10biosynthesisPDSS26q21NS[25]COQ24q21.23NS[26]COQ614q24.3NS[27]COQ916q21Renaltubulopathy[28]ADCK419q13.2NS[29,30]MitochondrialproteintranslationSARS2l19q13.2lProgressiverenalfailure,distaltubulopathy[31]MRPS223q23Renaltubulopathy[32]TSFM12q14.164Renaltubulopathy[33]PosttranslationalmodificationofmitochondrialproteinsXPNPEP322q13.2Interstitialfibrosis[34]RespiratorychainassemblyandfunctionBCS1L2q35PT,TIN[35]SURF199q34.2RTA[36]COX1017p12PT[37]TMEM708q21.11ProximalRTA[38]MitochondrialDNAdepletionMPV172p23.3Renalfailure[39]C10orf210q24.31PT[40]SUCLA213q14.2Methylmalonicaciduria[41]SUCLG12p11.2Methylmalonicaciduria[42]RRM2B8q22.3PT[43]DGUOK2p13.1Cystathioninuria[44]

Notes NS: nephrotic syndrome; RTA, renal tubular acidosis; PT: proximal tubulopathy; TIN: tubulointerstitial nephritis

本文例2表現(xiàn)為出生后即起病，多系統(tǒng)受累，累及腦、骨骼肌、心血管和腎臟，符合線粒體病的臨床特征。高通量測序發(fā)現(xiàn)檢出COQ6基因的純合p.R360W錯義突變，經(jīng)Sanger法驗證。家系突變分析顯示，患兒父母分別攜帶雜合p.R360W錯義突變。該突變經(jīng)在線軟件分析為有害性突變，且具有保守性，考慮為致病性突變，且為新發(fā)現(xiàn)突變。國外1項研究報道了5個家系12例COQ6基因突變患者，均為激素耐藥腎病綜合征，其中10例伴有感音神經(jīng)性耳聾，3例為先天性感音神經(jīng)性耳聾，5例出現(xiàn)感音神經(jīng)性耳聾年齡較晚(表4)，1例伴有驚厥，1例有腦白質(zhì)異常和驚厥，2例有共濟失調(diào)和面部畸形[27]。本文例2突出表現(xiàn)為神經(jīng)、心血管和腎臟等多系統(tǒng)受累，未發(fā)現(xiàn)感音神經(jīng)性耳聾，結(jié)合高通量測序結(jié)果，應(yīng)診斷為線粒體相關(guān)腎病，即COQ6基因相關(guān)腎小球疾病。COQ6基因相關(guān)腎小球疾病除腎臟受累外，還可以累及其他系統(tǒng)，最常見的腎外表現(xiàn)為感音神經(jīng)性耳聾，也可伴有心臟等系統(tǒng)表現(xiàn)。

雖然線粒體相關(guān)腎病累及腎小球時腎臟病理光鏡下主要是FSGS或塌陷性FSGS，少部分患者為球性硬化(表1、2、3和4)，但光鏡下腎臟病理改變并非線粒體相關(guān)腎病特征性改變[25,27,29,55]。有研究發(fā)現(xiàn)，電鏡下遠端腎小管和集合管細胞中出現(xiàn)顆粒狀腫脹的上皮細胞(GSECc)是線粒體相關(guān)腎病的特征改變，因IgA腎病、原發(fā)性FSGS和間質(zhì)性腎炎并無GSECc出現(xiàn)[55,56]。但目前文獻報道的病例并無該特征性改變。本文例1腎臟病理光鏡下顯示12腎小球有8個球性硬化，1個為FSGS，免疫熒光顯示少量IgG、IgM、IgA、C1q和C3沉積，為非特異性改變 ， 電鏡下顯示足細胞足突部分融合，未觀察到GSECc，與國外報道相似。本文例2未行腎活檢，腎功能異常與多個腎小球球性硬化嚴重病變相符，提示疾病進展較快。

COQ6和ADCK4基因突變等引起的線粒體相關(guān)腎病對激素和免疫抑制劑治療無反應(yīng)，易快速進展為終末期腎病，需要腎臟替代治療[27,29,49,57]。部分患兒經(jīng)輔酶Q10治療后臨床癥狀有所緩解。本文例2未給予激素治療，例1家長拒絕激素治療，2例基因診斷明確后均給予大劑量輔酶Q10(15～30 mg·kg-1·d-1)治療，雖然經(jīng)治療臨床癥狀改善不明顯，但隨訪期間臨床癥狀未見加重，而且腎功能監(jiān)測無明顯惡化，這也可能提示線粒體相關(guān)腎病(如腎小球球性硬化)可能不可逆。早期發(fā)現(xiàn)，早期干預(yù)有可能避免不可逆腎損害。

線粒體相關(guān)腎病雖然罕見，但該病已經(jīng)是兒童終末期腎病的重要病因之一[49,57]。提高對該病的認識，早期發(fā)現(xiàn)和早期干預(yù)該病，有助于兒童慢性腎臟病的防治。

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(本文編輯：丁俊杰)

Mitochondrial nephropathy in two children and literature review

LIGuo-min1,5,SUNLi1,5,SHENQian1,XUHong1,FANGXiao-yan1,CAOQi1,LIUHai-mei1,ZHAIYi-hui1,WUBing-bing2,LIUXue-guang3,YANGQing4

(1DepartmentofNephrologyandRheumatology,Children′sHospitalofFudanUniversity,Shanghai201102; 2MedicalTranslationalCenterofChildren′sHospitalofFudanUniversity,Shanghai201102; 3DepartmentofPathology,ShanghaiMedicalCollegeofFudanUniversity,Shanghai200023; 4The2ndAffiliatedHospitalandYuyingChildren′sHospitalofWenzhouMedicalUniversity,Wenzhou325027,China; 5hasequalcontribution)

XU Hong，E-mail:hxu@shmu.edu.cn

ObjectiveTo summarize and review the clinical data of two children with mitochondrial nephropathy so as to improve it′s knowledge. MethodsClinical data of two cases with mitochondrial nephropathy were summarized, including clinical manifestations, laboratory findings, renal pathological changes and family investigation. This study used next generation sequencing to screen 4 000 genes, including the 40 genes known to be associated with mitochondrial disease. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing and segregation analysis was performed using parental DNA samples.ResultsIn two cases, one is a boy, the other is a girl. Age onset of the girl was 11.7 years. She presented with proteinuria, renal dysfunction, no extrarenal symptoms and focal segmental glomerulosclerosis (FSGS) in renal biopsy. Heterozygous p.E447 and p.G601A mutations inNPHS1 and homozygous p.D209H mutation inADCK4 gene were detected and confirmed by next-generation sequencing and conventional Sanger sequencing, respectively. Family analysis showed that the girl had same genotype inNPHS1 gene with her father and sibling, and her homozygous p.D209H mutation inADCK4 gene was from parents. The boy presented with congenital heart disease and mental retardation after birth, and nephrotic syndrome in few months later. Homozygous p.R360W mutation inCOQ6 gene was identified and confirmed by next-generation sequencing and Sanger sequencing, respectively. Family analysis showed that homozygous p.R360W mutation in COQ6 gene inherited from his parents. Missense p.D209H and p.R360W mutations were damaging by prediction online PolyPhen and SIFT software. Protein multiple alignment showed site in p.D209H and p.R360W mutations both were conservative.ConclusionTwo cases with renal phenotype were caused by casual mutations inADCK4 andCOQ6 gene, respectively. These two cases could be diagnosed as mitochondrial nephropathy. One case with mutation inADCK4 gene presented with proteinuria, renal dysfunction, no extrarenal symptoms and FSGS in renal biopsy. The other with mutation inCOQ6 gene had nephrotic syndrome, except congenital heart disease and mental retardation.

Mitochondrial disease; Proteinuria; Nephrotic syndrome;ADCK4 gene;COQ6 gene

復(fù)旦大學(xué)附屬兒科醫(yī)院人才工程-學(xué)科帶頭人(1125)培育計劃

1 復(fù)旦大學(xué)附屬兒科醫(yī)院腎臟風(fēng)濕科 上海，201102；2 復(fù)旦大學(xué)附屬兒科醫(yī)院醫(yī)學(xué)轉(zhuǎn)化中心 上海，201102； 3 復(fù)旦大學(xué)上海醫(yī)學(xué)院病理教研室 上海，200023；4 溫州醫(yī)科大學(xué)附屬第二醫(yī)院育英兒童醫(yī)院 溫州，325027；5 共同第一作者

徐虹，E-mail:hxu@shmu.edu.cn

10.3969/j.issn.1673-5501.2015.06.006

2015-09-30

2015-11-27)