肖誠，劉潔穎,2，楊春如，于淼

綜 述

基因突變相關(guān)脂肪萎縮綜合征的研究進(jìn)展

肖誠1，劉潔穎1,2，楊春如1，于淼1

1. 中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院，北京協(xié)和醫(yī)院內(nèi)分泌科，國家衛(wèi)生健康委員會內(nèi)分泌重點(diǎn)實(shí)驗(yàn)室，北京 100730 2. 中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院，北京協(xié)和醫(yī)院醫(yī)學(xué)科學(xué)研究中心，疑難重癥及罕見病國家重點(diǎn)實(shí)驗(yàn)室，北京 100730

基因突變相關(guān)脂肪萎縮綜合征(lipodystrophy syndrome)是一組由A型核纖層蛋白(lamin A/C,)基因突變引起的常染色體顯性遺傳單基因疾病，以選擇性脂肪缺失伴胰島素抵抗等代謝異常為特征。本文總結(jié)了目前已報(bào)道的可引起脂肪萎縮綜合征的突變位點(diǎn)，及該突變位點(diǎn)導(dǎo)致的代謝并發(fā)癥、心血管異常、性腺軸紊亂、肌病、腎臟異常等多種臨床表現(xiàn)，闡述了基因致病性突變位點(diǎn)可能的致病機(jī)制及診療方法，以期為該疾病的基礎(chǔ)研究和臨床診治提供參考。

脂肪萎縮綜合征；基因突變；胰島素抵抗；代謝紊亂性疾??；致病機(jī)制

脂肪萎縮綜合征(lipodystrophy syndrome)是一組以脂肪選擇性不同程度丟失為特征的異質(zhì)性疾病，發(fā)病率約為1/1,000,000[1,2]。A型核纖層蛋白(lamin A/C,)基因突變相關(guān)脂肪萎縮綜合征包含全身性或部分性脂肪萎縮。其中部分性脂肪萎縮又名為家族性部分性脂肪萎縮綜合征型2型(familial partial lipodystrophy，F(xiàn)PLD2，OMIM#1516620)，該病多在青春期發(fā)病，典型表現(xiàn)為四肢和軀干皮下脂肪減少，內(nèi)臟和面頸部區(qū)域脂肪堆積。突變相關(guān)全身性脂肪萎縮則表現(xiàn)為全身脂肪減少，常與突變相關(guān)早衰綜合征重疊[1,3]。突變相關(guān)的脂肪萎縮綜合征可出現(xiàn)多種臨床表型，累及全身多系統(tǒng)，包括胰島素抵抗、糖尿病、重度高甘油三酯血癥、多囊卵巢綜合征(polycystic ovary syndrome，PCOS)等多種內(nèi)分泌代謝紊亂疾病，以及心血管、腎臟損害等[4]。

迄今為止至少存在500余種突變形式，可引起包括FPLD2在內(nèi)的十余種疾病，累及脂肪、心肌、骨骼肌、骨骼、皮膚、神經(jīng)等多種組織，統(tǒng)稱為核纖層蛋白病[5]。所編碼的A型核纖層蛋白(lamin A/C)是核膜內(nèi)側(cè)核纖層的重要組成蛋白，在維持細(xì)胞核結(jié)構(gòu)和調(diào)節(jié)轉(zhuǎn)錄因子方面發(fā)揮重要作用[6]。然而，突變相關(guān)脂肪萎縮的具體發(fā)病機(jī)制尚未完全闡明，目前臨床治療多為對癥[4,7,8]。對于脂肪萎縮綜合征來說，早期正確診斷至關(guān)重要，本文通過總結(jié)不同位點(diǎn)突變相關(guān)脂肪萎縮綜合征的臨床表現(xiàn)、主要致病機(jī)制和診療方法，以期為該病的基礎(chǔ)研究和臨床診治提供更多的遺傳學(xué)依據(jù)，最大程度地延緩疾病進(jìn)展，改善預(yù)后。

1 LMNA基因突變相關(guān)脂肪萎縮綜合征的致病基因與表型的關(guān)聯(lián)

基因突變相關(guān)脂肪萎縮綜合征可以出現(xiàn)多種臨床表現(xiàn)，其中糖脂代謝紊亂和心血管系統(tǒng)異常是最為常見的臨床表現(xiàn)，此外還包括性腺軸紊亂、肌病、腎臟病變以及皮膚病變等臨床表現(xiàn)。研究發(fā)現(xiàn)80%的FPLD2由第482位密碼子突變引起，如p.R482W，形成典型的FPLD2[9]。其他突變散布于整個基因，大多為錯義突變，無義突變、重復(fù)和剪接突變均有報(bào)道(http://www.umd.be/LMNA/)。FPLD2主要是由外顯子8和外顯子11發(fā)生的雜合或復(fù)合雜合突變引起[10]。

Lamin A/C主要由3個部分組成：氨基端頭部、羧基端尾部以及一個α螺旋的桿狀結(jié)構(gòu)域(包含C1a、L1、C1b、L12、C2區(qū)域)[11]。本文主要總結(jié)了既往研究中除482位密碼子外其他可引起脂肪萎縮綜合征的突變位點(diǎn)(圖1)，及各突變位點(diǎn)所在區(qū)域出現(xiàn)的突變比例(表1)。進(jìn)一步歸納了相應(yīng)的臨床表現(xiàn)，包括代謝并發(fā)癥、心血管異常表現(xiàn)、性腺軸紊亂、肌病、腎臟異常等(表2)，大部分致病突變均為雜合突變，少部分為純合突變。表3總結(jié)了表2中所有突變位點(diǎn)引起的臨床表現(xiàn)發(fā)生率，其中高脂血癥的發(fā)生率高達(dá)91.4%，糖尿病的發(fā)生率為88.5%，45.7%的突變位點(diǎn)會出現(xiàn)胰島素抵抗，性腺軸紊亂和肝臟脂肪變性的發(fā)生率分別為42.3%和42.9%，心臟相關(guān)的病變包括心臟傳導(dǎo)異常、心律失常、心肌病變、瓣膜病變、心力衰竭，發(fā)生率分別占11.4%，25.7%，31.4%，26.9%和17.1%。此外，肌病、腎臟病變和皮膚病變的分別占25.8%、22.9%和28.6%。

圖1 LMNA突變相關(guān)脂肪萎縮綜合征致病位點(diǎn)所在區(qū)域

表1 LMNA突變相關(guān)脂肪萎縮綜合征致病位點(diǎn)所在區(qū)域的比例

1.1 糖脂代謝紊亂性疾病

脂肪萎縮綜合征容易出現(xiàn)以胰島素抵抗為核心包括高血糖、高脂血癥、非酒精性脂肪肝病等在內(nèi)的多種代謝并發(fā)癥。一項(xiàng)源自土耳其關(guān)于FPLD2的研究顯示，與對照組相比，F(xiàn)PLD2患者的甘油三酯(triglyceride，TG)及血糖水平明顯升高，而高密度脂蛋白水平下降[24]。由于脂肪減少會突出肌肉外觀，因此相比男性而言，女性患者更容易辨別，其代謝并發(fā)癥也更嚴(yán)重。一項(xiàng)納入258例FPLD2患者的研究發(fā)現(xiàn)大多數(shù)男性患者TG水平為400 mg/dL或更低，而女性患者的TG平均水平達(dá)1000～2000 mg/dL，容易罹患急性胰腺炎等并發(fā)癥[61]。

1.2 心血管疾病異常

在脂肪萎縮綜合征中，心肌、節(jié)律傳導(dǎo)系統(tǒng)、心臟瓣膜和冠狀動脈等均可出現(xiàn)異常表現(xiàn)。攜帶突變的人群心律失?；蛐募〔∽兠磕甑陌l(fā)病率為8.43/1000人，高于未攜帶人群的6.38/1000人[62]。心肌病變通常表現(xiàn)為擴(kuò)張型心肌病、心臟傳導(dǎo)阻滯(Ⅰ度、Ⅱ度和Ⅲ度)、室上性心律失常(房撲、房顫)、室性心率失常(室顫、持續(xù)室速)、心動過緩-過速綜合征[63]、心力衰竭、左室心尖部室壁瘤等[64]，甚至出現(xiàn)猝死[65,19]。無干預(yù)的情況下，突變引起的心臟受累患者通常預(yù)后不佳。Meta分析顯示攜帶突變的人群猝死風(fēng)險(xiǎn)較普通人群升高3.7倍[66]。一項(xiàng)隨訪7年納入122名攜帶突變患者的研究更是證實(shí)了這些患者存在惡性室性心律失常的傾向，34%的患者出現(xiàn)持續(xù)性室性心律失常，48%的患者需要一級預(yù)防心源性猝死裝用植入式心臟復(fù)律除顫器[65]。當(dāng)突變的心肌病變患者在左室射血分?jǐn)?shù)≤45%或起搏百分比≥50%時(shí)，心臟再同步化治療有效[67]。

1.3 骨骼肌異常表現(xiàn)

突變可導(dǎo)致先天性肌營養(yǎng)不良、腓骨肌萎縮癥2B1型、肢帶型肌營養(yǎng)不良1B、常染色體顯性遺傳Emery-Dreifuss 型肌營養(yǎng)不良等，表現(xiàn)為頸軸肌、肩腓肌無力和肌萎縮，關(guān)節(jié)攣縮，脊柱畸形等異常[68]。此外，研究發(fā)現(xiàn)FPLD2患者的肌肉更加發(fā)達(dá)，肌肉活檢可發(fā)現(xiàn)1型和2型肌纖維肥大，以及出現(xiàn)一些非特異性改變[69]。在一些脂肪萎縮的患者中也會出現(xiàn)多種骨骼肌異常的表現(xiàn)。例如，一項(xiàng)關(guān)于p.R349W突變家系報(bào)道中，多名患者出現(xiàn)了肌痛以及脊柱側(cè)彎等病變[24]。p.R471G突變則可以引起肌無力和關(guān)節(jié)攣縮等異常表現(xiàn)[39]。p.R644C突變的患者則出現(xiàn)了肌痛、肌無力、肌萎縮、脊柱病變等幾乎所有骨骼肌病變的表現(xiàn)[57,58]。

1.4 性腺軸紊亂

不少研究報(bào)道了FPLD2患者存在性腺軸紊亂，以PCOS常見，少部分患者也可以出現(xiàn)月經(jīng)稀發(fā)[20]、高促性腺激素性腺功能減退癥[70]。在FPLD2中，除了與胰島素抵抗相關(guān)，PCOS可能還與游離脂肪酸積聚引起的卵巢脂毒性以及腹腔內(nèi)脂肪組織的堆積相關(guān)[71]。

1.5 腎臟異常表現(xiàn)

p.R349W突變的FPLD2家系中共有12名患者攜帶該突變，4名患者表現(xiàn)出不同程度的腎功能不全和蛋白尿，腎臟活檢病理顯示為局灶節(jié)段性腎小球硬化癥[72]。p.R482W突變的FPLD2患者腎臟活檢病理為2型系膜毛細(xì)血管增生性腎小球腎炎[73]。此外，存在糖尿病時(shí)還可引起糖尿病腎病的并發(fā)癥[34]。

表3 LMNA突變相關(guān)脂肪萎縮綜合征的臨床表現(xiàn)的比例

1.6 其他表現(xiàn)

一些較為少見的臨床表現(xiàn)包括如皮膚萎縮、硬化、黃瘤、天鵝絨淺棕色乳頭瘤增生性斑塊、皮贅等異常表現(xiàn)[12,40,43,48～50,53]；臍疝[42,49,50,52]、智力異常[39,48,50]、聽力下降[24,34,57, 58]在FPLD2患者中亦有報(bào)道。

2 LMNA基因突變相關(guān)脂肪萎縮綜合征的致病機(jī)制

關(guān)于突變產(chǎn)生組織特異性的表型，相同的突變位點(diǎn)可引起不同的疾病表型的具體機(jī)制尚不明確，但是根據(jù)目前已有的研究報(bào)道，主要致病機(jī)制大致分為以下三類[74](圖2)。

2.1 錯誤加工或未加工的核纖層蛋白A前體(prelamin A)積聚，產(chǎn)生細(xì)胞毒性

基因包含12個外顯子，經(jīng)過轉(zhuǎn)錄翻譯形成prelamin A，肽鏈的羧基端“CAAX”(C，半胱氨酸；A，脂肪族氨基酸；X，末端氨基酸)結(jié)構(gòu)域的半胱氨酸被法尼基轉(zhuǎn)移酶識別發(fā)生法尼基化，半胱氨酸再發(fā)生甲基酯化，然后由蛋白酶ZMPSTE24剪切掉包含“AAX”在內(nèi)的末端15個氨基酸，形成不含法尼基化殘基的成熟Lamin A[75,76]。突變后阻礙了prelamin A的成熟過程，法尼基化的prelamin A錨定在核膜上，容易導(dǎo)致核膜結(jié)構(gòu)紊亂，功能異常[77,78]。在一項(xiàng)研究中發(fā)現(xiàn)與對照組細(xì)胞相比，攜帶p.D47Y、p. L92F、p.L387V、p.R399H、p.L421P突變的成纖維細(xì)胞核形狀異常、增殖活性降低，細(xì)胞中prelamin A積聚，氧化應(yīng)激水平增加，線粒體呼吸鏈蛋白表達(dá)減少，細(xì)胞亦過早衰老。抑制prelamin A的法尼基化可以防止氧化應(yīng)激和細(xì)胞衰老[79]。此外，他汀類藥物或抗氧化劑預(yù)處理可以部分改善攜帶p.R482W突變的內(nèi)皮細(xì)胞功能[80]。

2.2 Lamin A/C與染色質(zhì)或蛋白之間的相互作用

2.2.1 減少膽固醇調(diào)節(jié)元件結(jié)合蛋白1(sterol regulatory element binding protein 1，SREBP1)表達(dá)

SREBP1是一種脂肪細(xì)胞轉(zhuǎn)錄因子，其激活對于啟動間充質(zhì)干細(xì)胞分化為脂肪細(xì)胞的至關(guān)重要。Lloyd等[81]首次鑒定SREBP1是Lamin A的一種新型互作因子，p. G465D、p.R482W和p.K486N顯著降低Lamin A與SREBP1的結(jié)合，減少了SREBP1表達(dá)，是引起代謝紊亂的原因之一。

圖2 LMNA突變相關(guān)脂肪萎縮綜合征的致病機(jī)制

2.2.2 miR-335抑制脂肪干細(xì)胞分化

microRNA是短鏈非編碼 RNA，通常在與3′非翻譯區(qū)結(jié)合后通過降解或翻譯沉默來下調(diào)靶mRNA表達(dá)。miR-335促進(jìn)成肌，抑制間充質(zhì)干細(xì)胞向脂肪細(xì)胞和骨細(xì)胞分化[82,83]。在野生型的脂肪干細(xì)胞成脂分化過程中，結(jié)合miR-335基因座，miR-335表達(dá)受抑制，而攜帶p.R482W突變的脂肪干細(xì)胞和源于FPLD2患者的成纖維細(xì)胞中miR-335表達(dá)升高，突變后失去了與miR-335的結(jié)合，從而使其發(fā)生持續(xù)轉(zhuǎn)錄，抑制脂肪干細(xì)胞分化[84]。

2.2.3哺乳動物雷帕霉素靶標(biāo)(mammalian target of rapamycin，mTOR)信號途徑

mTOR信號通路在調(diào)節(jié)脂肪細(xì)胞分化、脂質(zhì)代謝、產(chǎn)熱和脂肪因子合成與分泌中發(fā)揮關(guān)鍵作用。H222P/H222P小鼠擬似突變引起的骨骼肌、心肌異常表型，在該小鼠模型中應(yīng)用mTOR的抑制劑西羅莫司，激活了自噬水平，減緩了心功能減退[85]。–/–小鼠模型的脂肪減少與脂肪分解有關(guān)，雷帕霉素治療后脂肪分解減少，有助于改善全身代謝[86]。

2.2.4 Notch信號途徑

脂肪組織過表達(dá)Notch細(xì)胞內(nèi)結(jié)構(gòu)域(Notch intracellular domain, NICD)的C57BL/6J小鼠呈現(xiàn)多種代謝異常表現(xiàn)，且小鼠的白色脂肪含量明顯減低，出現(xiàn)異位脂肪沉積，呈現(xiàn)出類似脂肪萎縮的表型[87]。在人心臟間充質(zhì)干細(xì)胞中表達(dá)野生型或p.R482L，進(jìn)一步過表達(dá)NICD，相比野生組，突變組脂肪細(xì)胞分化能力下降，突變可能通過Notch信號通路影響脂肪細(xì)胞分化[88]。

2.2.5 轉(zhuǎn)化生長因子β(transforming growth factor- β, TGF-β)途徑

FPLD2患者的脂肪組織中TGF-β和細(xì)胞外基質(zhì)的失衡也是致病原因之一。與FPLD2患者類似，脂肪組織特異性表達(dá)p.R482Q突變小鼠的脂肪組織纖維化程度增加，細(xì)胞外基質(zhì)發(fā)生重塑，歸因于TGF-β和基質(zhì)金屬蛋白酶表達(dá)增加[89]。

2.3 細(xì)胞核及核膜結(jié)構(gòu)紊亂

幾乎所有的突變都會出現(xiàn)核形態(tài)的異常和核膜結(jié)構(gòu)的紊亂，如細(xì)胞核增大，核膜出現(xiàn)起泡、凹陷以及異常積聚，削弱了對外部刺激的抵抗力，也可能會改變與核纖層關(guān)聯(lián)域(Lamina associated domains，LADs)相關(guān)蛋白或DNA，進(jìn)而影響染色質(zhì)結(jié)構(gòu)[90,91]。

3 診斷和治療

遺傳分析有助于建立基因突變相關(guān)脂肪萎縮綜合征的診斷并指導(dǎo)進(jìn)一步治療。治療上尚無針對性和使脂肪組織再生的方法，主要是預(yù)防或改善脂肪萎縮綜合征的并發(fā)癥。

3.1 基礎(chǔ)治療方法：飲食和運(yùn)動

由于脂肪萎縮綜合征存在多種代謝相關(guān)的并發(fā)癥，因此正確的生活方式是治療的基石，鼓勵大多數(shù)患者遵循均衡飲食，在沒有特定禁忌癥的情況下進(jìn)行運(yùn)動[4,92]。

3.2 瘦素療法

外源性補(bǔ)充瘦素，可能有助于改善FPLD2的代謝情況。一項(xiàng)含22例FPLD2患者的前瞻性研究顯示瘦素類似物美曲普汀改善了TG和糖化血紅蛋白[7]。在中至重度的低瘦素血癥FPLD2患者中應(yīng)用美曲普汀，TG以及胰島素敏感性和分泌指數(shù)也得到了有效改善[93]。

3.3 美容治療

通過接受自體脂肪組織移植或真皮填充劑的植入，可以改善面部或乳房外觀。頭部、頸部或外陰的多余脂肪可以通過手術(shù)減少或通過吸脂術(shù)減少。

3.4 針對合并癥的治療

3.4.1 糖尿病

二甲雙胍是一線降糖和改善胰島素抵抗用藥。噻唑烷二酮類藥物可能有助于改善代謝并發(fā)癥[1]。胰島素可有效降低高血糖，但可能需要極大劑量胰島素[4]。新型降糖藥物如胰高糖素樣肽-1受體激動劑、二肽基肽酶4抑制劑和鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白-2抑制劑，均能夠有效降低多種心血管危險(xiǎn)因素，但這些藥物尚缺乏在脂肪萎縮綜合征中系統(tǒng)性的研究[92]。Roux-en-Y胃旁路代謝手術(shù)有助于減輕體重及改善代謝[94]。

3.4.2 高脂血癥

他汀類藥物應(yīng)作為一線用藥。對于重度高TG的患者，可考慮貝特類藥物。Omega-3-脂肪酸也被廣泛使用，但這一特定人群中的功效缺乏充足的證據(jù)[1]。其他新的血脂異常藥物如前蛋白轉(zhuǎn)化酶枯草桿菌蛋白酶9型抑制劑尚未在脂肪萎縮的患者中進(jìn)行研究。

3.4.3 非酒精性脂肪性肝病

在飲食和運(yùn)動方法的基礎(chǔ)上，噻唑烷二酮類藥物和維生素E活性有助于改善肝功能或肝脂肪變性[95,96]，但這些藥物缺乏在脂肪萎縮綜合征患者中的研究。

4 結(jié)語與展望

突變相關(guān)脂肪萎縮綜合征的致病位點(diǎn)分布于整個區(qū)域，突變類型多變，致病機(jī)制復(fù)雜，涉及多種信號通路，但該病特異性的分子機(jī)制仍不清晰，需要進(jìn)一步研究來揭示不同突變位點(diǎn)的特異性致病機(jī)制。該病臨床表現(xiàn)多樣，異質(zhì)性較高，在臨床工作中容易漏診、誤診，貽誤病情，影響預(yù)后。本文通過總結(jié)突變相關(guān)脂肪萎縮綜合征的致病位點(diǎn)相關(guān)臨床表現(xiàn)以及可能的致病機(jī)制，有助于提高臨床醫(yī)生中對該疾病的認(rèn)識，有利于早期診斷和管理，最大程度改善患者預(yù)后。也為將來深入研究突變引起的核纖層蛋白病奠定了基礎(chǔ)。隨著研究的深入，相信未來將更深層次地認(rèn)識突變相關(guān)脂肪萎縮綜合征并為患者提供更好的治療措施。

[1] Garg, A. Clinical review#: lipodystrophies: genetic and acquired body fat disorders, 2011, 96(11): 3313–3325.

[2] Garg A. Lipodystrophies, 2000, 108(2): 143– 152.

[3] Mann JP, Savage DB. What lipodystrophies teach us about the metabolic syndrome, 2019, 129(10): 4009–4021.

[4] Brown RJ, Araujo-Vilar D, Cheung PT, Dunger D, Garg A, Jack M, Mungai L, Oral EA, Patni N, Rother KI, von Schnurbein J, Sorkina E, Stanley T, Vigouroux C, Wabitsch M, Williams R, Yorifuji T, The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline, 2016, 101(12): 4500–4511.

[5] Schreiber KH, Kennedy BK. When lamins go bad: nuclear structure and disease, 2013, 152(6): 1365–1375.

[6] Osmanagic-Myers S, Foisner R. The structural and gene expression hypotheses in laminopathic diseases-not so different after all, 2019, 30(15): 1786– 1790.

[7] Sekizkardes H, Cochran E, Malandrino N, Garg A, Brown RJ. Efficacy of metreleptin treatment in familial partial lipodystrophy due to PPARG vspathogenic variants, 2019, 104(8): 3068– 3076.

[8] Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin, 2015, 100(5): 1802–1810.

[9] Bertrand AT, Chikhaoui K, Yaou RB, Bonne G. Clinical and genetic heterogeneity in laminopathies, 2011, 39(6): 1687–1692.

[10] Subramanyam L, Simha V, Garg A. Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozygous missense lamin A/C mutations, 2010, 78(1): 66–73.

[11] Strelkov SV, Schumacher J, Burkhard P, Aebi U, Herrmann H. Crystal structure of the human lamin A coil 2B dimer: implications for the head-to-tail association of nuclear lamins, 2004, 343(4): 1067–1080.

[12] Mory PB, Crispim F, Kasamatsu T, Gabbay MA, Dib SA, Moisés RS. Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygousp.T10I mutation, 2008, 52(8): 1252–1256.

[13] Jiajue R, Feng K, Wang R, Xia W. Recurrent femoral fractures in a boy with an atypical progeroid syndrome: a case report, 2020, 106(3): 325–330.

[14] Fukaishi T, Minami I, Masuda S, Miyachi Y, Tsujimoto K, Izumiyama H, Hashimoto K, Yoshida M, Takahashi S, Kashimada K, Morio T, Kosaki K, Maezawa Y, Yokote K, Yoshimoto T, Yamada T. A case of generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement with short and long-term monitoring of the metabolic and endocrine profiles, 2020, 67(2): 211–218.

[15] Sahinoz M, Khairi S, Cuttitta A, Brady GF, Rupani A, Meral R, Tayeh MK, Thomas P, Riebschleger M, Camelo-Piragua S, Innis JW, Bishr Omary M, Michele DE, Oral EA. Potential association of-associated generalized lipodystrophy with juvenile dermatomyositis, 2018, 4: 6.

[16] Hussain I, Patni N, Ueda M, Sorkina E, Valerio CM, Cochran E, Brown RJ, Peeden J, Tikhonovich Y, Tiulpakov A, Stender SRS, Klouda E, Tayeh MK, Innis JW, Meyer A, Lal P, Godoy-Matos AF, Teles MG, Adams-Huet B, Rader DJ, Hegele RA, Oral EA, Garg A. A novel generalized lipodystrophy-associated progeroid syndrome due to recurrent heterozygousp.T10I mutation, 2018, 103(3): 1005–1014.

[17] Cardona-Hernández R, Suárez-Ortega L, Torres M. Difficult to manage diabetes mellitus associated with generalized congenital lipodystrophy. Report of two cases., 2011, 74(2): 126–130.

[18] Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP, Hegele RA. Novel lamin A/C gene () mutations in atypical progeroid syndromes, 2004, 41(4): 304–308.

[19] Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene, 2002, 112(7): 549–555.

[20] Decaudain A, Vantyghem MC, Guerci B, Hécart AC, Auclair M, Reznik Y, Narbonne H, Ducluzeau PH, Donadille B, Lebbé C, Béréziat V, Capeau J, Lascols O, Vigouroux C. New metabolic phenotypes in laminopathies:mutations in patients with severe metabolic syndrome, 2007, 92(12): 4835– 4844.

[21] Türk M, Wehnert M, Schr?der R, Chevessier F., Multisy-stem disorder and limb girdle muscular dystrophy caused byp.R28W mutation, 2013, 23(7): 587–590.

[22] Ambonville C, Bouldouyre MA, Laforêt P, Richard P, Benveniste O, Vigouroux C. A complex case of diabetes due to LMNA mutation., 2017, 38(10): 695–699.

[23] Kutbay NO, Yurekli BS, Onay H, Altay CT, Atik T, Hekimsoy Z, Saygili F, Akinci B. A case of familial partial lipodystrophy caused by a novel lamin A/C () mutation in exon 1 (D47N), 2016, 29: 37–39.

[24] Akinci B, Onay H, Demir T, Savas-Erdeve ?, Gen R, Simsir IY, Keskin FE, Erturk MS, Uzum AK, Yaylali GF, Ozdemir NK, Atik T, Ozen S, Yurekli BS, Apaydin T, Altay C, Akinci G, Demir L, Comlekci A, Secil M, Oral EA. Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy, 2017, 72: 109–119.

[25] van der Kooi AJ, Bonne G, Eymard B, Duboc D, Talim B, Van der Valk M, Reiss P, Richard P, Demay L, Merlini L, Schwartz K, Busch HF, de Visser M. Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy, 2002, 59(4): 620–623.

[26] Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet Jr HJ, Spudich S, De Girolami U, Seidman JG, Seidman C, Muntoni F, Müehle G, Johnson W, McDonough B. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease, 1999, 341(23): 1715–1724.

[27] He GY, Yan Z, Sun L, Lv Y, Guo W, Gang XK, Wang G. Diabetes mellitus coexisted with progeria: a case report of atypical Werner syndrome with novelmutations and literature review, 2019, 66(11): 961–969.

[28] Cecchetti C, D'Apice MR, Morini E, Novelli G, Pizzi C, Pagotto U, Gambineri A. Case report: an atypical form of familial partial lipodystrophy type 2 due to mutation in the rod domain of lamin A/C, 2021, 12: 675096.

[29] Lanktree M, Cao H, Rabkin SW, Hanna A, Hegele RA., Novelmutations seen in patients with familial partial lipodystrophy subtype 2 (FPLD2; MIM 151660), 2007, 71(2): 183–186.

[30] Araújo-Vilar D, Victoria B, González-Méndez B, Barreiro F, Fernández-Rodríguez B, Cereijo R, Gallego-Escuredo JM, Villarroya F, Pa?eda-Menéndez A. Histological and molecular features of lipomatous and nonlipomatous adipose tissue in familial partial lipodystrophy caused bymutations, 2012, 76(6): 816–824.

[31] Mahdi L, Kahn A, Dhamija R, Vargas HE. Hepatic steatosis resulting from-associated familial lipodystrophy, 2020, 7(4): e00375.

[32] Motegi S, Yokoyama Y, Uchiyama A, Ogino S, Takeuchi Y, Yamada K, Hattori T, Hashizume H, Ishikawa Y, Goto M, Ishikawa O., First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygousmutation, 2014, 41(12): 1047–1052.

[33] Renard D, Fourcade G, Milhaud D, Bessis D, Esteves-Vieira V, Boyer A, Roll P, Bourgeois P, Levy N, De Sandre-Giovannoli A. Novelmutation in atypical Werner syndrome presenting with ischemic disease, 2009, 40(2): e11–e14.

[34] Mory PB, Crispim F, Freire MB, Salles JE, Valério CM, Godoy-Matos AF, Dib SA, Moisés RS. Phenotypic diversity in patients with lipodystrophy associated withmutations, 2012, 167(3): 423– 431.

[35] Jeru I, Vatier C, Vantyghem MC, Lascols O, Vigouroux C.-associated partial lipodystrophy: anticipation of metabolic complications, 2017, 54(6): 413– 416.

[36] van Tintelen JP, Hofstra RM, Katerberg H, Rossenbacker T, Wiesfeld ACP, du Marchie Sarvaas GJ, Wilde AAM, van Langen IM, Nannenberg EA, van der Kooi AJ, Kraak M, van Gelder IC, van Veldhuisen DJ, Vos Y, van den Berg MP, Working Group on Inherited Cardiac Disorders, line 27/50, Interuniversity Cardiology Institute of The Netherlands. High yield ofmutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics, 2007. 154(6): 1130–1139.

[37] Fountas A, Giotaki Z, Dounousi E, Liapis G, Bargiota A, Tsatsoulis A, Tigas S. Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C?>?Tmutation, 2017, 2017: 0017–0049.

[38] Andre P, Schneebeli S, Vigouroux C, Lascols O, Schaaf M, Chevalier P. Metabolic and cardiac phenotype characteri-zation in 37 atypical Dunnigan patients with nonfarnesy-lated mutated prelamin A, 2015, 169(4): 587–593.

[39] Muschke P, K?lsch U, Jakubiczka S, Wieland I, Brune T, Wieacker P. The heterozygousmutation p.R471G causes a variable phenotype with features of two types of familial partial lipodystrophy, 2007, 143A(23): 2810–2814.

[40] Saha B, Lessel D, Hisama FM, Leistritz DF, Friedrich K, Martin GM, Kubisch C, Oshima J. A novelmutation causes altered nuclear morphology and symptoms of familial partial lipodystrophy (Dunnigan variety) with progeroid features, 2010, 1(3): 127–132.

[41] Wehnert MS, Feuer A, Wasner C, Hoeltzenbein M. Novel P485R mutation inpresenting with features of a progeroid syndrome., 2004, 14: 591–592.

[42] de Andrade NXS, Adiyaman SC, Yuksel BD, Ferrari CT, Eldin AJ, Saydam BO, Altay C, Sharma P, Bhave N, Little A, McKeever P, Onay H, Ozkal S, Secil M, Yenerel MN, Akinci B, Oral EA. Unusual presentations of- associated lipodystrophy with complex phenotypes and generalized fat loss: when the genetic diagnosis uncovers novel features., 2020, 6(2): e79–e85.

[43] Morel CF, Thomas MA, Cao H, O'Neil CH, Pickering JG, Foulkes WD, Hegele RA. Asplicing mutation in two sisters with severe Dunnigan-type familial partial lipodystrophy type 2, 2006, 91(7): 2689–2695.

[44] Chirico V, FerraùV, Loddo I, Briuglia S, Amorini M, Salpietro V, Lacquaniti A, Salpietro C, Arrigo T.gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response, 2014, 40(3): 224–228.

[45] Savage DB, Soos MA, Powlson A, O'Rahilly S, McFarlane I, Halsall DJ, Barroso I, Thomas EL, Bell JD, Scobie I, Belchetz PE, Kelly WF, Schafer AJ. Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in thegene, 2004, 47(4): 753–756.

[46] Chan D, McIntyre AD, Hegele RA, Don-Wauchope AC. Familial partial lipodystrophy presenting as metabolic syndrome, 2016, 10(6): 1488–1491.

[47] Guillín-Amarelle C, Sánchez-Iglesias S, Mera A, Pintos E, Castro-Pais A, Rodríguez-Ca?ete L, Pardo J, Casanueva FF, Araújo-Vilar D. Inflammatory myopathy in the context of an unusual overlapping laminopathy, 2018, 62(3): 376–382.

[48] Patni N, Hatab S, Xing C, Zhou Z, Quittner C, Garg A. A novel autosomal recessive lipodystrophy syndrome due to homozygousvariant, 2020, 57(6): 422–426.

[49] Patni N, Xing C, Agarwal AK, Garg A. Juvenile-onset generalized lipodystrophy due to a novel heterozygous missensemutation affecting lamin C, 2017, 173(9): 2517–2521.

[50] Montenegro Jr RM, Costa-Riquetto AD, Fernandes VO, Montenegro A, de Santana LS, Jorge AAL, Karbage L, Aguiar LB, Carvalho FHC, Teles MG, d'Alva CB. Homozygous and heterozygous nuclear lamin A p.R582C mutation: different lipodystrophic phenotypes in the same kindred, 2018, 9: 458.

[51] Kao KT, Zacharin M. An adolescent girl referred with Cushing syndrome—does she or does she not have the syndrome?, 2016, 29(1): 109– 112.

[52] Garg A, Vinaitheerthan M, Weatherall PT, Bowcock AM. Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene, 2001, 86(1): 59–65.

[53] Soyaltin UE, Simsir IY, Akinci B, Altay C, Adiyaman SC, Lee K, Onay H, Oral EA. Homozygousp.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy, 2020, 6: 13.

[54] Vigouroux C, MagréJ, Vantyghem MC, Bourut C, Lascols O, Shackleton S, Lloyd DJ, Guerci B, Padova G, Valensi P, Grimaldi A, Piquemal R, Touraine P, Trembath RC, Capeau J. Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy, 2000, 49(11): 1958–1962.

[55] Hegele RA, Cao H, Anderson CM, Hramiak IM. Heterogeneity of nuclear lamin A mutations in Dunnigan- type familial partial lipodystrophy, 2000. 85(9): 3431–3435.

[56] Araújo-Vilar D, Lado-Abeal J, Palos-Paz F, Lattanzi G, Bandín MA, Bellido D, Domínguez-Gerpe L, Calvo C, Pérez O, Ramazanova A, Martínez-Sánchez N, Victoria B, Costa-Freitas AT. A novel phenotypic expression associated with a new mutation ingene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy, 2008, 69(1): 61–68.

[57] Resende ATP, Martins CS, Bueno AC, Moreira AC, Foss-Freitas MC, de Castro M. Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2, 2019, 91(1): 94–103.

[58] Rankin J, Auer-Grumbach M, Bagg W, Colclough K, Nguyen TD, Fenton-May J, Hattersley A, Hudson J, Jardine P, Josifova D, Longman C, McWilliam R, Owen K, Walker M, Wehnert M, Ellard S. Extreme phenotypic diversity and nonpenetrance in families with thegene mutation R644C, 2008, 146A(12): 1530–1542.

[59] Monteiro LZ, Foss-Freitas MC, Júnior Montenegro RM, Foss MC. Body fat distribution in women with familial partial lipodystrophy caused by mutation in the lamin A/C gene, 2012, 16(1): 136–138.

[60] Le Dour C, Schneebeli S, Bakiri F, Darcel F, Jacquemont ML, Maubert MA, Auclair M, Jeziorowska D, Reznik Y, Béréziat V, Capeau J, Lascols O, Vigouroux C. A homo-zygous mutation of prelamin-A preventing its farnesy-lation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin-A, 2011, 96(5): E856–E862.

[61] Hussain I, Patni N, Garg A. Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease, 2019, 51(2): 202–212.

[62] Lazarte J, Jurgens SJ, Choi SH, Khurshid S, Morrill VN, Weng L-C, Nauffal V, Pirruccello JP, Halford JL, Hegele RA, Ellinor PT, Lunetta KL, Lubitz SA.Variants and Risk of Adult-Onset Cardiac Disease, 2022, 80(1): 50–59.

[63] Gl?cklhofer CR, Steinfurt J, Franke G, Hoppmann A, Glantschnig T, Perez-Feliz S, Alter S, Fischer J, Brunner M, Rainer PP, K?ttgen A, Bode C, Odening KE. A novelnonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family, 2018, 20(12): 2003–2013.

[64] Forissier JF, Bonne G, Bouchier C, Duboscq-Bidot L, Richard P, Wisnewski C, Briault S, Moraine C, Dubourg O, Schwartz K, Komajda M. Apical left ventricular aneurysm without atrio-ventricular block due to a lamin A/C gene mutation, 2003, 5(6): 821–825.

[65] Kumar S, Baldinger SH, Gandjbakhch E, Maury P, Sellal JM, Androulakis AF, Waintraub X, Charron P, Rollin A, Richard P, Stevenson WG, Macintyre CJ, Ho CY, Thompson T, Vohra JK, Kalman JM, Zeppenfeld K, Sacher F, Tedrow UB, Lakdawala NK. Long-term arrhythmic and nonarrhythmic Outcomes of Lamin A/C Mutation carriers, 2016, 68(21): 2299–2307.

[66] van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D, Rossenbacker T, Heidbüchel H, de Visser M, Crijns HJ, Pinto YM. Meta-analysis of clinical characteristics of 299 carriers ofgene mutations: do lamin A/C mutations portend a high risk of sudden death?, 2005, 83(1): 79–83.

[67] Sidhu K, Castrini AI, Parikh V, Reza N, Owens A, Tremblay-Gravel M, Wheeler MT, Mestroni L, Taylor M, Graw S, Gigli M, Merlo M, Paldino A, Sinagra G, Judge DP, Ramos H, Mesubi O, Brown E, Turnbull S, Kumar S, Roy D, Tedrow UB, Ngo L, Haugaa K, Lakdawala NK., The response to cardiac resynchronization therapy incardiomyopathy, 2022, 24(4): 685–693.

[68] Menezes MP, Waddell LB, Evesson FJ, Cooper S, Webster R, Jones K, Mowat D, Kiernan MC, Johnston HM, Corbett A, Harbord M, North KN, Clarke NF. Importance and challenge of making an early diagnosis in- related muscular dystrophy, 2012, 78(16): 1258–1263.

[69] Spuler S, Kalbhenn T, Zabojszcza J, van Landeghem FK, Ludtke A, Wenzel K, Koehnlein M, Schuelke M, Lüdemann L, Schmidt HH. Muscle and nerve pathology in Dunnigan familial partial lipodystrophy, 2007, 68(9): 677–683.

[70] McPherson E, Turner L, Zador I, Reynolds K, Macgregor D, Giampietro PF. Ovarian failure and dilated cardiomyopathy due to a novel lamin mutation, 2009, 149A(4): 567–572.

[71] Gambineri A, Zanotti L. Polycystic ovary syndrome in familial partial lipodystrophy type 2 (FPLD2): basic and clinical aspects, 2018, 9(1): 392–397.

[72] Thong KM, Xu YX, Cook J, Takou A, Wagner B, Kawar B, Ong AC. Cosegregation of focal segmental glomerulosclerosis in a family with familial partial lipodystrophy due to a mutation in, 2013, 124(1–2): 31–37.

[73] Owen KR, Donohoe M, Ellard S, Clarke TJ, Nicholls AJ, Hattersley AT, Bingham C. Mesangiocapillary glomerulonephritis type 2 associated with familial partial lipodystrophy (Dunnigan-Kobberling syndrome), 2004, 96(2): c35–c38.

[74] Nicolas HA, Akimenko MA, Tesson F. Cellular and animal models of striated muscle laminopathies, 2019, 8(4): 291.

[75] Young SG, Fong LG, Michaelis S. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesis, 2005, 46(12): 2531– 2558.

[76] Rusi?ol AE, Sinensky MS. Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors, 2006, 119(Pt 16): 3265–3272.

[77] Broers JLV, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ. Nuclear lamins: laminopathies and their role in premature ageing, 2006, 86(3): 967–1008.

[78] Cau P, Navarro C, Harhouri K, Roll P, Sigaudy S, Kaspi E, Perrin S, De Sandre-Giovannoli A, Lévy N. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective, 2014, 29: 125–147.

[79] Caron M, Auclair M, Donadille B, Béréziat V, Guerci B, Laville M, Narbonne H, Bodemer C, Lascols O, Capeau J, Vigouroux C. Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence, 2007, 14(10): 1759–1767.

[80] Bidault G, Garcia M, Vantyghem MC, Ducluzeau PH, Morichon R, Thiyagarajah K, Moritz S, Capeau J, Vigouroux C, Béréziat V. Lipodystrophy-linkedp.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction, 2013, 33(9): 2162–2171.

[81] Lloyd DJ, Trembath RC, Shackleton S. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies, 2002, 11(7): 769–777.

[82] Meyer SU, Sass S, Mueller NS, Krebs S, Bauersachs S, Kaiser S, Blum H, Thirion C, Krause S, Theis FJ, Pfaffl MW. Integrative analysis of microRNA and mRNA data reveals an orchestrated function of microRNAs in skeletal myocyte differentiation in response to TNF-α or IGF1, 2015, 10(8): e0135284.

[83] Tomé M, López-Romero P, Albo C, Sepúlveda JC, Fernández-Gutiérrez B, Dopazo A, Bernad A, González MA. miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells, 2011, 18(6): 985–995.

[84] Oldenburg A, Briand N, S?rensen AL, Cahyani I, Shah A, Moskaug J, Collas P. A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus, 2017, 216(9): 2731–2743.

[85] Choi JC, Muchir A, Wu W, Iwata S, Homma S, Morrow JP, Worman HJ. Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation, 2012, 4(144): 144ra102.

[86] Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, MacKay VL, An EH, Strong R, Ladiges WC, Rabinovitch PS, Kaeberlein M, Kennedy BK. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival, 2012, 4(144): 144ra103.

[87] Chartoumpekis DV, Palliyaguru DL, Wakabayashi N, Khoo NK, Schoiswohl G, O'Doherty RM, Kensler TW. Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice, 2015, 4(7): 543–550.

[88] Perepelina K, Dmitrieva R, Ignatieva E, Borodkina A, Kostareva A, Malashicheva A. Lamin A/C mutation associated with lipodystrophy influences adipogenic differentiation of stem cells through interaction with Notch signaling, 2018, 96(3): 342– 348.

[89] Le Dour C, Wu W, Béréziat V, Capeau J, Vigouroux C, Worman HJ. Extracellular matrix remodeling and transforming growth factor-β signaling abnormalities induced by lamin A/C variants that cause lipodystrophy, 2017, 58(1): 151–163.

[90] Muchir A, Medioni J, Laluc M, Massart C, Arimura T, van der Kooi AJ, Desguerre I, Mayer M, Ferrer X, Briault S, Hirano M, Worman HJ, Mallet A, Wehnert M, Schwartz K, Bonne G. Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations, 2004, 30(4): 444–450.

[91] Vigouroux C, Guénantin AC, Vatier C, Capel E, Le Dour C, Afonso P, Bidault G, Béréziat V, Lascols O, Capeau J, Briand N, Jéru I. Lipodystrophic syndromes due tomutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives, 2018, 9(1): 235–248.

[92] Foss-Freitas MC, Akinci B, Luo YY, Stratton A, Oral EA. Diagnostic strategies and clinical management of lipodystrophy, 2020, 15(2): 95–114.

[93] Vatier C, Fetita S, Boudou P, Tchankou C, Deville L, Riveline J, Young J, Mathivon L, Travert F, Morin D, Cahen J, Lascols O, Andreelli F, Reznik Y, Mongeois E, Madelaine I, Vantyghem M, Gautier J, Vigouroux C. One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes, 2016, 18(7): 693–697.

[94] Grundfest-Broniatowski S, Yan JL, Kroh M, Kilim H, Stephenson A. Successful treatment of an unusual case of FPLD2: the role of Roux-en-Y gastric bypass-case report and literature review, 2017, 21(4): 739–743.

[95] Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis, 2012, 35(1): 66–75.

[96] Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, 2010, 362(18): 1675–1685.

Advances in lipodystrophy syndrome caused bygene mutation

Cheng Xiao1, Jieying Liu1,2, Chunru Yang1, Miao Yu1

Lipodystrophy syndrome caused bygene mutation is a group of autosomal dominant monogenic diseases, characterized by selective fat loss and metabolic abnormalities with insulin resistance. In this review, we summarize the clinical manifestations caused by multiple pathogenicmutations reported so far, including metabolic complications, cardiovascular abnormalities, gonadal axis disorders, myopathy, and renal abnormalities. Meanwhile, we also clarify the possible pathogenic mechanism, diagnosis, and treatment, in order to improve the understanding of the disease and to provide a reference for basic research and clinical diagnosis and treatment of this disease.

lipodystrophy syndrome;gene mutation; insulin resistance; metabolic disorders; pathogenic mechanisms

2022-06-30;

2022-09-06;

2022-09-20

國家自然科學(xué)基金項(xiàng)目(編號：82170855)和科技部國家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目(編號：2020YFC2004505，2018YFC2001105)資助[Supported by the National Nature Science Foundation of China (No. 82170855) and the National Key Research and Development Program (Nos. 2020YFC2004505, 2018YFC2001105)]

肖誠，在讀博士研究生，專業(yè)方向：內(nèi)分泌與代謝病方向。E-mail: jz_xiaocheng@163.com

于淼，博士，教授，研究方向：內(nèi)分泌與代謝病方向。E-mail: yumiaoxh@163.com

10.16288/j.yczz.22-225

(責(zé)任編委: 周紅文)