張星雨，祝天喻，張清榮，郭雪江，王鋮，靳光付，胡志斌

精子發(fā)生障礙的遺傳學研究進展

張星雨，祝天喻，張清榮，郭雪江，王鋮，靳光付，胡志斌

南京醫(yī)科大學生殖醫(yī)學國家重點實驗室，南京 211166

育齡人群中約15%的夫妻被不孕不育困擾，其中男方因素導致的不孕不育約占50%。男性不育通常由精子發(fā)生障礙導致，呈現(xiàn)為少、弱、畸形精子癥，最嚴重的是無精子癥。本文以精子發(fā)生障礙為主線，重點綜述了非梗阻性無精子癥和畸形精子癥的遺傳學病因研究。近年來，隨著高通量芯片和測序技術的快速發(fā)展，無精子癥和畸形精子癥的遺傳學因素得以深入的揭示與解析。圍繞無精子癥，全基因組關聯(lián)研究與高通量測序研究揭示了一批非梗阻性無精子癥的風險位點和致病基因；圍繞畸形精子癥，全外顯子測序等研究鑒定了一系列致病基因，極大地豐富了精子鞭毛多發(fā)性形態(tài)異常等精子畸形的遺傳學病因。大量致病基因的發(fā)現(xiàn)，促進了男性不育病理機制的闡明。全面而深入地了解精子發(fā)生障礙中的遺傳因素，對男性不育的診斷、臨床治療和遺傳咨詢具有重要的意義。

精子發(fā)生；遺傳因素；非梗阻性無精子癥；精子畸形；鞭毛多發(fā)性形態(tài)異常

在全球范圍內，約有15%的夫婦受不孕不育困擾，其中男性因素約占50%[1]。男性不育主要由于精子發(fā)生障礙導致。精子發(fā)生過程包括精原細胞有絲分裂、精母細胞減數(shù)分裂以及精子細胞變形形成蝌蚪狀精子的過程，其中任一環(huán)節(jié)發(fā)生缺陷都會導致男性不育[2]。精子發(fā)生障礙在臨床上主要體現(xiàn)為無精子癥、少精子癥、畸形精子癥和/或弱精子癥，其中最嚴重的是無精子癥。無精子癥是指在射出的精液中完全不存在精子，包括梗阻性無精子癥(obstructive azoospermia, OA)和非梗阻性無精子癥(nonobstructive azoospermia, NOA)[3]。OA患者的睪丸通常具有正常的精子產(chǎn)生能力，由于梗阻原因導致精子輸送異常，從而表現(xiàn)為無精子癥，而NOA則是由于睪丸內精子發(fā)生障礙導致?；尉影Y主要是精子的頭部或尾部畸形，最近關注較多的精子鞭毛多發(fā)性形態(tài)異常(multiple morphological abnor-malities of the flagella, MMAF)[4]，主要是呈現(xiàn)為精子尾部畸形。引起精子發(fā)生障礙的因素主要包括環(huán)境因素和遺傳因素。近年來基因組芯片和測序等高通量技術的快速發(fā)展，促進了復雜疾病的致病基因發(fā)現(xiàn)，精子發(fā)生障礙中非梗阻性無精子癥與畸形精子癥越來越多的相關基因被鑒定(表1)。本文主要圍繞非梗阻性無精子癥和畸形精子癥的遺傳學因素研究進展進行綜述。

1 非梗阻性無精子癥的遺傳學研究

NOA是男性不育中精子發(fā)生障礙最嚴重的一種疾病，在男性不育患者中約占10%[3]。目前已知的NOA的遺傳因素包括染色體數(shù)量和結構異常以及精子發(fā)生功能基因異常。

1.1 染色體數(shù)量/結構異常與NOA

染色體異常指染色體的數(shù)目或結構異常。在NOA患者中最常見染色體數(shù)目異常的是Klinefelter 綜合征(47, XXY)[46]。Y染色體長臂上的微缺失會破壞精子發(fā)生關鍵基因的完整性，可解釋約5~10%的NOA患者的病因[47,48]。此外，Lu等[49]通過將NOA患者與健康人對比發(fā)現(xiàn)Y染色體單倍型類群(Y chromosome haplogroups, Y-hgs) K*與O3e*兩種類群在兩組中的分布差異具有統(tǒng)計學意義：Y-hg K*人群中出現(xiàn)DAZ (Deleted in Azoospermia)多拷貝(>4)的頻率顯著高于Y-hg O3e*人群，提示DAZ的拷貝數(shù)過多可能是Y-hg K*人群導致NOA的原因之一。

1.2 NOA的致病突變和致病基因

目前人們對于NOA的致病突變/基因的認識十分局限，已確定的NOA致病基因較少[50]。近年來，高通量測序技術推動了NOA的致病突變的發(fā)現(xiàn)。

Laura 等[5]通過全外顯子組測序(whole-exome sequencing, WES)技術在患有NOA的同胞兄弟中發(fā)現(xiàn)(nanos C2HC-type zinc finger 2)的突變，該基因可維持精原細胞數(shù)目，發(fā)生突變后則無法保證精原細胞的數(shù)目，最終導致SCOS。據(jù)報道，、和等基因在精母細胞減數(shù)分裂過程中參與了重組、染色體交叉互換、DNA雙鏈斷裂的修復，它們失去功能后會造成減數(shù)分裂阻滯，從而導致NOA的發(fā)生[5-11]。

已被發(fā)現(xiàn)和證實可導致NOA的基因尚十分局限，但是隨著測序的發(fā)展與應用，將有更多NOA致病基因被逐漸解析。這對于生殖方向的基礎研究和臨床方向的基因診斷方法開發(fā)均意義重大。

1.3 NOA的易感基因與易感位點

全基因組關聯(lián)研究(genome-wide association study, GWAS)可通過對比病例組和對照組全基因組單核苷酸多態(tài)性(single nucleotide polymorphism, SNP)發(fā)現(xiàn)疾病相關的SNP位點。比如Hu等[51]人首次開展NOA的多階段GWAS研究，在2927名NOA患者和5734名健康對照中鑒定出3個NOA風險SNP位點：rs12097821、rs2477686和rs10842262；Zhao等[52]通過GWAS發(fā)現(xiàn)主要組織相容性復合體(major histocompatibility complex, MHC)基因座上的兩個SNP位點rs3129878和rs498422與人群NOA的易感性存在顯著關聯(lián)。

隨后，Hu等[53]又發(fā)現(xiàn)4個與NOA關聯(lián)的新易感位點：rs7194、rs7099208、rs13206743和rs3000811。其中rs3000811附近易感基因(CDC42 binding protein kinase alpha)在果蠅中存在同源基因。將果蠅基因敲降后，雄性果蠅出現(xiàn)不育表型；rs7099208位于(family with sequence similarity 160 member B1)的末位內含子中。主要表達在精原細胞與圓形精子中，而在NOA患者睪丸中表達降低甚至缺失，因此，rs7099208位點可能通過影響的表達影響NOA發(fā)生的風險[54]。

在上述研究發(fā)現(xiàn)的易感位點中，rs7194、rs3129878和rs498422均位于MHC區(qū)域[51,52]，于是Huang等[55]對MHC區(qū)域開展精細定位(fine mapping)分析，發(fā)現(xiàn)rs4997052與NOA易感性有關，這為揭示MHC區(qū)域與NOA易感性間的遺傳機制提供了新的認識。此外，Qin等[56]結合精子發(fā)生關鍵基因對NOA-GWAS數(shù)據(jù)進行深入挖掘，發(fā)現(xiàn)了3個NOA的易感位點，定位至3個基因，其中(rs2126986)和(rs7226979)會增加人群對NOA的易感性，(rs1406714)則相反。

對于多基因參與的復雜性疾病而言，低頻遺傳變異的數(shù)目遠超過常見遺傳變異，其遺傳貢獻尚不明確。Ni等[57]系統(tǒng)研究低頻遺傳變異與中國男性患NOA風險的關聯(lián)，發(fā)現(xiàn)3個與NOA發(fā)病風險顯著相關的低頻遺傳變異。其中rs2298090及rs200847762均顯著降低了中國漢族男性患NOA的風險，而rs11754464 G>A與NOA發(fā)病風險的增加顯著相關。該研究發(fā)現(xiàn)說明了低頻變異在精子發(fā)生過程中的重要作用。

由此可見，通過大量樣本的關聯(lián)研究能夠從人群層面系統(tǒng)鑒定NOA的易感位點和易感基因，有助于研究者更加深入而全面地認識NOA發(fā)生的遺傳機制。

2 畸形精子癥的遺傳學研究

精子細胞經(jīng)過精子形成過程產(chǎn)生精子的過程中，會經(jīng)歷一系列細胞生物學事件。如細胞核的濃縮、頂體的形成、組蛋白被魚精蛋白的替換、胞質殘余體的丟棄及鞭毛的發(fā)生，其中變化最大的是精子尾部。在精子變形期間，精子細胞中心體遷移到細胞表面，遠端中心粒發(fā)出微管形成軸絲，導致精細胞質膜從細胞突出。然后形成鞭毛并延伸到生精小管管腔中，精子鞭毛的組裝依賴鞭毛內轉運(intra-flagellar transport, IFT)機制，可選擇性地將特定的分子轉運到特定的位置，從而保證鞭毛的正常結構。

精子尾部可分為頸段、中段、主段和末段。頸段連接精子尾和頭。中段位于頸段和主段之間，主要由軸絲、ODF、MS等組成。軸絲由周邊的9對二聯(lián)微管和一對中央微管組成，是典型的“9+2”結構，前接頸段，后向尾部延伸，幾乎貫穿精子尾部。軸絲的每對二聯(lián)微管由A型亞微管和B型亞微管組成，每個A型亞微管向下一個B型亞微管伸出2個短臂，稱動力蛋白臂(dynein arm)，包括IDA和ODA，均由重鏈(heavy chains, HC)、中鏈(intermediate chains, IC)、中輕鏈(light-intermediate chains, LIC)、輕鏈(light chains, LC)以及許多調節(jié)蛋白組成。ODA與精子運動密切相關。IDA影響到精子鞭毛拍擊的力量和頻率。同時A亞微管向中央微管發(fā)出絲狀的結構，稱放射輻(radial spokes, RS)，起到連接中央微管和二聯(lián)微管的作用(圖1)。

2.1 大頭精子癥(macrozoospermia)

大頭精子癥在1977年被首次報道[58]，是指精子頭部尺寸大于正常精子頭部，具有多條鞭毛，幾乎全部為四倍體，通常伴隨少精癥出現(xiàn)。它是一種罕見的不育病因，在不育癥患者中占比不到1%。目前，只有(aurora kinase C)基因被證實是大頭精子癥的遺傳學病因[12]。編碼減數(shù)分裂細胞中染色體分離所需的絲氨酸/蘇氨酸蛋白激酶成分，對于減數(shù)分裂染色體分離和胞質分裂至關重要[12]。大多數(shù)大頭精子癥是由于基因3號外顯子中胞嘧啶的純合缺失(c.144delC)。該突變導致蛋白質的截短而缺少激酶結構域，從而影響減數(shù)分裂，并且當兩次減數(shù)分裂都受到影響時，精子為四倍體[12]。

2.2 圓頭精子癥(globozoospermia)

圓頭精子癥特征是產(chǎn)生圓頭、無頂體的精子。高爾基復合體產(chǎn)生前頂體囊泡，前頂體囊泡融合在核膜附近形成頂體。精子頂體含有的多種水解酶對于精卵結合及整個受精過程至關重要，因此當精子頭部頂體缺陷時將導致嚴重的男性不育。圓頭精子癥非常少見，僅影響0.1%的不育男性[1]。在小鼠模型中，有50多個不同的基因突變會導致圓頭精子癥的發(fā)生。但在人類中，僅4個基因(、、和)的突變被證明與該疾病有關[13-15]。(dpy-19 like 2)突變是圓頭精子癥最常見(60%~80%)的遺傳缺陷，該基因位于第12號染色體長臂，編碼的蛋白是精子發(fā)生過程中頭部延長和頂體形成所必需的，其功能缺失將導致這些過程的阻滯[59]。研究者發(fā)現(xiàn)在小鼠中敲除會導致類似的圓頭精子癥表型[60]。在患者中最常見的突變方式是整個基因的完全缺失。為了探究該基因缺失導致圓頭精子癥的分子機制，Guo等[61]通過高通量蛋白質組學分析缺失的圓頭精子與正常精子之間的蛋白表達差異，發(fā)現(xiàn)SPACA1、IZUMO1、ZPBP和PLCZ1等多個參與精子變形與功能的蛋白表達異常，為人類圓頭精子癥的發(fā)生機制提供了線索。此外，(spermatogenesis associated 16)(protein interacting with PRKCA 1)與(zona pellucida binding protein)的突變也會導致人類圓頭精子癥[14-16]。

圖1 精子鞭毛超微結構及主要的MMAF相關結構蛋白表達定位

FS：纖維鞘(fibrous sheath)；ODA：外側動力蛋白臂(outer dynein arm)；IDA：內側動力蛋白臂(inner dynein arm)；CP：中央微管(central pair)；ODF：外周致密纖維(outer dense fiber)；MTDs：二聯(lián)微管(microtubule doublets)；RS：放射輻(radial spokes)；IFT：鞭毛內轉運(intraflagellar transport)。

2.3 無頭精子癥(acephalic spermatozoa, AS)

AS是男性不育癥中最嚴重的類型之一，無頭精子癥患者的精液中大部分是無頭的精子，還有少部分是頭尾連接異常的精子。根據(jù)超微結構觀察精子頸部的斷裂位點，可分為Ⅰ、Ⅱ、Ⅲ三種亞型：Ⅰ型AS是在兩個中心粒之間斷開的，但相關基因尚未被報道，仍有待研究。Ⅱ型的斷裂點在細胞核與近端的中心粒之間，目前已證實(SAD1 and UNC84 domain containing 5)、(polyamine modulated factor 1 binding protein 1)和(hook microtubule tethering protein 1)三個基因的突變與Ⅱ型AS的發(fā)生有關[17-19]。Ⅲ型無頭精子的斷裂點在遠端中心粒和精子鞭毛中段之間，如(bro-modomain testis associated)突變導致的AS[20]。

在動物與人類中突變均可導致Ⅱ型AS。SUN5是基底小體(basal body)對面核膜上的跨膜蛋白，具有促進植入窩與基底小體之間的連接和相互作用，確保頭部錨定在精子尾。突發(fā)生變可造成無頭精子的形成[17]。是另一個Ⅱ型AS基因，其蛋白在植入窩與基底小體上均有表達。PMFBP1蛋白定位于SUN5與TSGA10之間，三者形成的結構在精子頸部作為蛋白支架起到連接頭尾的作用。當三者之間無法正常相互作用時，便會導致AS的發(fā)生[18,62]。此外，的突變也會導致Ⅱ型AS的發(fā)生[19]。

Ⅲ型AS基因也逐漸被發(fā)現(xiàn)。Li等[20]報道基因突變導致的無頭精子尾部中段缺少MS，可能是人類無頭精子癥發(fā)生的致病基因。據(jù)報道在西方國家突變常造成嚴重的少精癥甚至無精癥。但是，已有報道稱該基因的RNA剪接位點純合突變與無頭精子的發(fā)生有關[63]。與上述機制類似，在其他AS病例中，還發(fā)現(xiàn)了(testis specific 10)基因突變導致的無頭精子伴隨MS受損[21]。

2.4 精子鞭毛多發(fā)性形態(tài)異常

精子鞭毛多發(fā)性形態(tài)異常(MMAF)是最常見的精子畸形，它是精子鞭毛缺失、過短、不規(guī)則或卷曲等癥狀的總稱。在電鏡下，MMAF精子鞭毛的軸絲與軸絲旁結構顯示出嚴重的錯亂[64]。近幾年，隨著Khelifa等[24]在2014年報道突變可引起MMAF，關于MMAF的遺傳學研究成果不斷涌現(xiàn)，目前已經(jīng)可以解釋約60%的MMAF患者的遺傳學病因[38,45]。精子鞭毛超微結構的穩(wěn)定對維持鞭毛的形態(tài)和功能至關重要。研究表明，精子鞭毛的多個結構發(fā)生異常，均可導致MMAF[64](圖1)。下面將按精子鞭毛的形成與結構，總結MMAF的遺傳學研究進展。

2.4.1 中心體缺陷的相關基因

中心體對于精子鞭毛的發(fā)生起到至關重要的作用。中心體存在于所有的真核細胞中，由一對相互垂直的中心粒構成。中心體參與胞內許多的功能，比如形成細胞骨架、形成有絲分裂的紡錘體。在鞭毛或纖毛形成過程中，中心體遷移到細胞外圍，以中心粒為基體啟動軸絲的組裝。

(centrosomal protein 135)編碼一種中心體蛋白，目前僅報道一例MMAF病人與突變有關[22]，并且該病人的精子無法通過ICSI與卵子形成正常受精卵，研究認為這與精子中心體參與調控受精卵第一次分裂有關。最近Lv等[23]在兩名MMAF患者中發(fā)現(xiàn)(DAZ interacting zinc finger protein 1)突變也會導致中心粒功能障礙，造成精子尾部鞭毛的缺失，并在小鼠模型中得到驗證。但是該報道并未提及此類精子是否能夠成功ICSI，目前仍需更多的相關研究以闡明中心體功能障礙對于輔助生殖的影響。

2.4.2 動力蛋白臂蛋白缺陷的相關致病基因

近期研究發(fā)現(xiàn)了一些進化保守的動力蛋白臂相關基因及其蛋白的缺失可導致MMAF。Khelifa等[24]在20名北非MMAF患者中發(fā)現(xiàn)有6位患者的基因存在純合突變。隨后，多項研究相繼報道MMAF患者存在突變[65-67]。內側動力蛋白臂(IDA)由七分子復合物組成，以3-2-2的排列方式組合并對應于三種不同類型的球形頭部(IDA1、IDA2和IDA3)。(在小鼠中的同源基因)敲除小鼠的IDA3頭部缺失，表明DNAH1蛋白是IDA3的組成部分。研究者推測突變使IDA3的頭部缺失，造成輪輻的錨定位點缺失，使中央微管的附著減弱，形成精子尾部的畸形[68]。后續(xù)研究表明，所在家族的多個成員突變均可導致MMAF，包括[25][26]DNAH8[27]以及[28]

2.4.3 動力蛋白臂關聯(lián)蛋白缺陷的相關致病基因

在內側動力蛋白臂中存在一個與之關聯(lián)的有兩個頭部的動力蛋白，稱作I1 dynein (dynein f)，簡稱I1[69]，而近年來在MMAF病人中報道的、和等基因與衣藻中編碼內側動力蛋白臂關聯(lián)蛋白的基因是同源基因。

2017年，Zhang等[29]首次證實(cilia and flagella associated protein 43)和突變會導致精子MMAF表型，并懷疑具有相似的作用。2019年，接連兩篇報道證實與缺陷是導致MMAF的原因之一[70,71]。另外基因突變的患者精子有MMAF的表現(xiàn)，并在敲除鼠中得到驗證[30]。

CFAP70蛋白則屬于外側動力蛋白臂相關聯(lián)的復合物，對于ODA的組裝或活性至關重要[72]。2019年，Beurois等[31]在167名MMAF患者的隊列中發(fā)現(xiàn)2例患者攜帶突變。

2.4.4 RS缺陷的相關致病基因

RS是二聯(lián)微管的A型微管向中央微管發(fā)出的絲狀結構。RS將中央微管與周圍的二聯(lián)管連接起來。(或)蛋白主要定位在RS，2018年Kherraf等[73]首次在78名MMAF患者的隊列中鑒定到7人攜帶的突變。越來越多的證據(jù)表明突變是導致MMAF的原因之一：Auguste等[32]報道3名MMAF患者攜帶突變，伴隨MS結構異常；Li等[74]在65名漢族MMAF患者中證實3人攜帶突變導致MMAF。此外，還有報道稱基因突變會使中心微管與放射輻缺陷，導致MMAF[75]。

2.4.5 軸絲及其周圍結構缺陷的相關致病基因

軸絲幾乎貫穿精子尾部，其周圍結構包括MS、ODF和FS。許多報道稱MMAF的精子存在軸絲或其周圍結構的結構紊亂，提示MMAF的發(fā)生可能與軸絲及其周圍結構相關的基因缺陷有關。

早在2003年，Eddy等[76]闡述了兩種A型激酶錨定蛋白AKAP3和AKAP4 (A-kinase anchoring protein 3, 4)作為結構蛋白在FS中含量最為豐富。其中AKAP3在圓形精子時期參與組成FS的基本結構，而AKAP4在精子發(fā)生的晚期表達參與FS的最終形成[77]。和基因突變會導致患者出現(xiàn)MMAF類似表型[34]，并證實突變小鼠具有MMAF表型。

最近，He等[78]在90名MMAF患者中發(fā)現(xiàn)5人攜帶突變，并通過小鼠模型證實突變是導致MMAF的原因。此外(fibrous sheath interacting protein 2)基因突變會導致MMAF的發(fā)生[36,79]。上述基因的突變均會導致精子鞭毛的FS結構完全紊亂，其次軸絲也出現(xiàn)中心微管和動力蛋白缺失等缺陷。

2.4.6 鞭毛內轉運失調的相關致病基因

IFT相關蛋白對于精子發(fā)生起重要作用，如小鼠突變模型顯示其蛋白在精子的鞭毛形成過程中是必需的。近期，研究者發(fā)現(xiàn)人類IFT相關基因突變可導致MMAF的發(fā)生：

(tetratricopeptide repeat domain 21A)，又稱，編碼的蛋白包含19個TPR結構域。2019年，Liu等[37]在兩個不同的MMAF隊列中共鑒定到5位患者攜帶的突變。突變鼠模型也具有MMAF表型，但機制尚不清楚。與類似。最近兩組研究報道該基因突變與MMAF有關[38,80]，突變患者的精子呈現(xiàn)明顯的MMAF表型。

最近研究發(fā)現(xiàn)，(sperm flagellar 2)突變與MMAF的發(fā)生有關[39,81,82]。雄性小鼠生殖細胞特異性敲除基因后具有MMAF表型，證明SPEF2蛋白為精子尾部的形成所需。此外研究者還發(fā)現(xiàn)該蛋白與細胞質動力蛋白1 (cytoplasmic Dynein1)相互作用，參與IFT過程[83]。突變也會造成人類的MMAF發(fā)生，并且在小鼠中得到了驗證[40]，伴有精子頭部的異常。小鼠睪丸蛋白質組學分析顯示CFAP69與SPEF2存在關聯(lián)。此外，(WD repeat domain 19)是IFT復合物的一個核心成分，該基因突變的病人也表現(xiàn)出MMAF癥狀，主要為短尾和卷尾[41]。

2.4.7 其他鞭毛相關基因

一些具體功能定位尚不清晰的基因突變可導致MMAF，如(glutamine rich 2)，(adenylate kinase 7)和(armadillo repeat containing 2)等。2019年兩組研究共鑒定到4名MMAF患者的基因發(fā)生突變[42,43]，突變小鼠模型具有MMAF表型[43]。在睪丸中特異表達，可以維持精子發(fā)生功能蛋白的穩(wěn)定性。在成熟精子中，QRICH2蛋白與Tubulin一起沿著精子鞭毛分布。進一步研究發(fā)現(xiàn)，QRICH2蛋白可以通過抑制泛素化通路提高AKAP3、TTSK4等蛋白的穩(wěn)定性，而這兩種蛋白的缺失會導致精子尾部缺陷[77,84]。編碼一種腺苷酸激酶，催化兩分子ADP反應生成一分子ATP和一分子AMP。2018年的一項研究稱人類突變會造成MMAF癥狀[44]。最近Coutton等[45]在168位MMAF病人的隊列中發(fā)現(xiàn)5位患者的基因發(fā)生突變，之后在小鼠中敲除后，小鼠精子也表現(xiàn)出MMAF和雄性不育，證明了突變導致MMAF。

3 結語與展望

精子發(fā)生障礙的遺傳病因研究是人類生殖健康的重要內容。得益于基因芯片和高通量測序等高通量技術的快速發(fā)展，精子發(fā)生障礙的遺傳學研究取得了重大進展。如圍繞精子發(fā)生障礙最嚴重的無精子癥，利用GWAS和高通量測序等技術研究基于大樣本人群揭示了多個疾病的風險位點和易感基因；畸形精子癥若呈現(xiàn)為均一類型的精子畸形，通常由遺傳學異常導致，深度測序的廣泛使用，促進了一系列致病基因的發(fā)現(xiàn)，也是近期男性不育遺傳學病因研究的熱點領域。然而，已鑒定到的致病突變位點大多位于基因編碼區(qū)，而基因的調控序列與非編碼區(qū)域/基因的改變，以及環(huán)境基因交互作用對精子發(fā)生障礙的影響仍然需要進一步的研究。致病與易感基因的發(fā)現(xiàn)為臨床男性不育病因學闡明、治療方法的研發(fā)以及遺傳咨詢等均有著重要意義。

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Progress in the genetic studies of spermatogenesis abnormalities

Xingyu Zhang, Tianyu Zhu, Qingrong Zhang, Xuejiang Guo, Cheng Wang, Guangfu Jin, Zhibin Hu

,,

About 15% couples suffer from infertility, half of which are caused by male factors. Male infertility usually manifests as teratozoospermia, oligospermia and/or asthenospermia, of which the most severe form is azoospermia. In this review, we summarize the recent progress in the study of genetic factors involved in nonobstructive azoospermia and teratozoospermia, Recently, with the rapid development of high-throughput chips and sequencing technologies, many genetic factors of spermatogenesis have been discovered and analyzed. For the nonobstructive azoospermia, genome-wide association studies (GWAS) and high-throughput sequencing revealed many risk loci of nonobstructive azoospermia. For the teratozoospermia, the application of whole-exome sequencing (WES) revealed a series of disease-causing genes, greatly enriching our knowledge of teratozoospermia including multiple morphological abnormalities of the flagella (MMAF). The discovery of lots of disease genes helped the characterization of the pathological mechanisms of male infertility. Therefore, a comprehensive and in-depth understanding of genetic factors in spermatogenesis abnormalities will play important roles in the clinical diagnosis, treatment and genetic counseling of male infertility.

spermatogenesis; genetics; nonobstructive azoospermia (NOA); teratozoospermia; multiple morphological abnormalities of the flagella (MMAF)

2020-12-17;

2021-03-16

國家重點研發(fā)計劃項目(編號：2016YFA0503300)[supported by the National Key R&D Program of China (No. 2016YFA0503300)]

張星雨，在讀本科生，專業(yè)方向：預防醫(yī)學。E-mail: xingyuzhang@njmu.edu.cn

胡志斌，教授，研究方向：生殖醫(yī)學。E-mail: zhibin_hu@njmu.edu.cn

10.16288/j.yczz.20-343

2021/4/8 10:42:52

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210407.1424.004.html

(責任編委: 劉默芳)