临床特征.

原发性纤毛运动障碍 (primary ciliary dyskinesia，PCD)与内脏位置异常, 精子运动异常, 纤毛功能结构异常有关 导致粘液和细菌在呼吸道滞留，引起慢性 耳鼻窦肺部疾病.超过 75%的足月的患有PCD的新生儿有 ‘新生儿呼吸窘迫症’ 需要辅助供氧几天至几周. 慢性呼吸道感染, 发生在幼年早期,导致和成人表现相似的支气管扩张. 鼻塞和鼻窦炎, 发生在幼年早期, 持续到成人. 慢性/反复性耳道感染, 发生在大多数年幼儿童身上, 和短暂的或者后来不可逆的听力丧失有关. 全内脏反位(所有内脏器官镜像反转并没有明显的生理影响)表现在 40%-50% 的患有PCD的个体上; 内脏异位(正常情况下不对称的结构左右不协调 可以导致严重的畸形)大概有12%的表现.几乎所有患有PCD的男性 由于精子活动异常而不育.

诊断/检验.

PCD的诊断可以通过临床的 表型 和通过纤毛超微结构分析或通过 分子遗传学检测. 大概三分之二的先证者可以被诊断通过 表现出与PCD有联系的32个基因型中的一个 双等位基因的 致病变异型.

管理.

治疗临床表现: 积极的措施以使粘液更干净 (胸背叩击和体位引流, 震荡背心, 呼吸动作帮助远端呼吸道的清洁) 和迅速的抗生素疗法以治疗呼吸道细菌感染 (支气管炎, 鼻窦炎, 和中耳炎);并考虑肺叶切除以治疗局部支气管扩张; 肺移植以治疗终末期肺病; 鼻窦手术治疗广泛的鼻窦感染; 考虑用PE管放置法处理慢性中耳炎;按需要可用 语言障碍矫正和助听器. 按需要可用外科手术以治疗 先天的 心脏病. ICSI (胞质内的精子注射) 或通过捐精 (AIDS)人工授精以治疗男性不育.预防次级并发症: 日常免疫接种 (包括流感疫苗和肺炎双球菌疫苗) 防止呼吸感染; 宣传教育控制感染 包括注意洗手,避免接触病人 ，正确的 清洁/消毒 呼吸设备;呼吸道疾病早用抗生素(由之前的呼吸道状况决定).

监督: 肺脏学家跟踪监视肺功能和痰中的病原体并评估肺病程度/级数; 对于那些有慢性中耳炎的人,直到青少年前的日常听力评估.

需避免的药剂/环境: 止咳药; 接触呼吸病原, 烟草烟雾, 和其他空气污染以及呼吸道刺激.

遗传咨询.

PCD遗传方式为 常染色体隐性遗传 .  受累的 个体的父母必然是杂合子，因此携带一个 等位基因 和一个 致病性变异. 杂合子 (携带者) 无症状. 理论上,受累的个体的每个同胞有25%的概率 受累,有 50% 的概率是无症状的  携带者, 有 25% 的概率是既不受累也不是携带者. 如果家庭中的致病变异型已知，高危亲属的带菌体实验和有受累风险的孕期产前诊断是可行的.

推测性结论

原发性纤毛不动症 (PCD) 可通过以下（但不限于）的临床表现判断:

• 慢性的耳-鼻窦-肺疾病
  • 慢性湿咳有痰
  • 慢性喘气气困
  • 肺功能测试有阻塞性肺病
  • 患有PCD个体中常见病原持续扩大感染
  • 胸片发现有慢性异常
  • 胸部 CT 扫描发现支气管扩张
  • 鼻窦x光照片发现有慢性全鼻窦炎
  • 慢性中耳炎,大多数显著发生在学龄前儿童
  • 新生儿呼吸窘迫, 尽管任期妊娠
  • 从新生儿期开始慢性鼻塞
• 内脏位置异常 可能是一下任一种情况:
  • 单侧性缺陷 (全内脏器官镜面反转但没有明显生理影响)
  • 心房不定位
  • 内脏异位 (正常情况下不对称器官左右不协调,通常临床分类为无脾 [主要表现为双侧右侧器官, 或右房异构] 或 多脾 [主要变现为双侧左侧器官或左房异构]) [Zhu et al 2006]
• 杵状指 典型与支气管扩张有关
• 男性不育

建立诊断

诊断一个 先证者 有原发性纤毛不动症可基于临床症状和 有已知的与PCD有关的32个基因型中双等位基因的 致病突变型 (见 Table 1A, Table 1B). 如果诊断不能通过 分子遗传学检测建立, 纤毛诊断 可以使用; 然而, 应该指出大概30%的患有PCD的个体纤毛没有微结构异常, 这是以前诊断的金标准.在很多病例中需要诊断测试面板  [Lucas & Leigh 2014].当需要用

 分子遗传学检测 诊断PCD时, 临床医生需要考虑到大多数致病突变型出现在 Table 1A包含的基因中, 致病突变很少在 Table 1B包含的基因中, 超过三分之一的明确判断出有PCD的个体没有已知的可辨认的在32个基因中的致病突变型.

纤毛微结构分析

透射电子显微镜鉴定纤毛微结构缺陷需要呼吸上皮活性组织检查 , 通常获得通过刷或刮鼻甲内表面或者通过支气管镜检刷支气管表面 [MacCormick et al 2002, Chilvers et al 2003]. 大约30%的临床表型 有PCD和鼻一氧化氮浓度低的群体有正常的纤毛微结构(其中很多诊断确认都是通过鉴定 双等位基因的 致病突变在 Table 1A 或 Table 1B所列的基因之一上) [Knowles et al 2013a].动力蛋白臂缺损经常由特定的突变

基因. 见 Table 2 (pdf). 最普遍的原发性纤毛不动症微结构缺损定义如下 (Figure 1) [Knowles et al 2013a, Davis et al 2015]:

Figure 1.

纤毛横断面 A. 纤毛示意图揭示 ‘9+2’ 排列结构九个外周微管二联体环绕中央一对微管 B. 代表正常纤毛的电子显微镜图像来自 (更多...)

• 变短 和/或 缺失仅外周动力蛋白臂 (明确的微结构缺损中~55% , 或所有PCD中的 38.5% )
• 变短或缺失内外动力蛋白臂 (明确的显微结构缺损中~15% , 或所有PCD中的 10.5%)
• 微管 (轴丝) 解体与内动力蛋白臂和中央复合体缺失有关 (明确的微结构缺损中的5%-20%,或所有PCD中的  ~14% )
• 中央复合体缺失或破坏 (中央微管对和/或 径向轴条蛋白) (明确的微结构缺损中的~10% , 或所有PCD中的 7% )
• 变短和/或缺失仅内动力蛋白臂  (罕见)
• 纤毛稀少 (仅有很少的纤毛)有或没有正常的微结构 (罕见).

注意: (1) 评价纤毛微结构的专业知识是被需要的为了区别初级（基因）缺损和由于暴露在不同环境和传染性病原体产生的获得性缺损. (2) 经典的卡塔格内综合症可有内脏转位, 鼻窦炎, 和支气管扩张没有明显的微结构缺损被观察报道. 现在知道一些患有经典的卡塔格内综合症的家庭有 双等位基因的 致病突变于 DNAH11 (位点 CILD7).想了解更多信息有关于纤毛微结构病例与突变的

 基因, 见 Table 2 (pdf).更多信息有关于其他评估测试作为PCD的筛选或支持测试, 点 这 (pdf).

临床描述

原发性纤毛不动症(PCD) 表现为: (1) 纤毛结构功能异常，基因缺陷，导致粘液和细菌滞留在呼吸道引起慢性的耳-鼻窦-肺疾病; 以及 (2)鞭毛的结构异常导致精子活动性能异常 .

肺病. 肺病的程度和严重度因人而异 [Marthin et al 2010]. 这种可变性一定程度上反应出 基因型 (见 基因型-表型相关性).超过75%足月的患有PCD的新生儿有呼吸窘迫需要辅助供氧几天至几周，然后，在这个年龄很少被诊断出 [Noone et al 2004, Ferkol & Leigh 2006, Mullowney et al 2014].慢性呼吸道感染在幼年早期出现

. 大多数儿童全年有慢性咳嗽; 慢性鼻窦炎和鼻塞 (经常伴有粘膜炎和明显的鼻引流)在生命的第一个月开始 经常在出生.痰中明显产出口咽的菌落 , 流感嗜血杆菌,肺炎双球菌, 和 金黄葡萄球菌 在幼年早期开始产生, 之后是绿脓杆菌(起初是光滑型后是粘液型)变得更加普遍. 尽管在儿童时期很罕见, 非结核分支杆菌感染发生在超过10%的成人上 [Noone et al 2004, Davis et al 2015].慢性呼吸道感染导致支气管扩张可能会出现在一些年幼儿童身上成人身上几乎都会发生

[Noone et al 2004, Brown et al 2008, Davis et al 2015].一部分有慢性呼吸道感染的成人在肺部有钙沉积

, 结果导致,咳出钙小石  (碎石) [Kennedy et al 2006].一些人在中年发展到肺病末期一部分人因此接受肺移植

.呼吸疾病攻击患有PCD的个体发生在幼年早期，得到合适的治疗肺病的恶化会减缓

.

鼻塞和鼻窦感染 在幼年早期发生并持续到成年 [Noone et al 2004, Leigh et al 2009].

慢性/反复性耳部感染, 在大部分患有PCD的幼童身上发生，到学龄期变得少发. 在很多婴儿和幼童身上, 慢性中耳炎会引起短暂的耳聋可能会影响说话能力. 如果不治疗, 中耳炎可能引起不可逆的耳聋 [Hadfield et al 1997, Majithia et al 2005].

不育. 几乎所有患有PCD的男性是不育的因其精子不具有正常的运动功能.一些患有的PCD的女性可以正常的生育

; 其他女性生育功能受损并且子宫外孕的风险增加因其输卵管处纤毛功能受损 [Afzelius 2004].

器官位置异常

• 全内脏反位 (所有的内脏器官镜面反转并没有明显的生理影响)在接近40%-50% 的患有PCD的个体中观察到.
• 内脏异位 (也叫做 "心房不定位") 在患有PCD个体中的大约12%表现出来 [Kennedy et al 2006, Shapiro et al 2014a]. 内脏异位,正常情况下不对称器官左右不协调, 不同于全内脏反位经常在临床上被诊断为无脾 (主要是双侧均系右侧结构,或右侧异构 ) 或多脾 (主要是双侧均系左侧结构,或左侧异构).
  对那些有内脏异位的患者, 先天的 心血管畸形是很常见很复杂的, 并且经常会致死. 特定的与内脏异位有关的心血管缺陷包括心房异构, 大血管转位, 右室双出口, 异常静脉回流, 下腔静脉缺如, 和两侧都有上腔静脉 [Zhu et al 2006].
  肺异构, 经常是无症状的, 可以是右侧异构(双侧三叶肺并有双侧动脉支气管) 或左侧异构 (两侧肺及其肺叶肺门都是正常的左肺的特征).
  胃可能居右; 肝可能居中, 或者左右叶可能颠倒.
  肠袢不正常旋转可能导致肠梗阻或肠扭结 (血管阻塞).
  中枢神经系统,骨骼 ,和生殖泌尿系统畸形也可能会发生 .

其他. 患有PCD的个体在罕见的情况下可能会有脑积水，反映出室管膜纤毛功能异常 [Wessels et al 2003, Kosaki et al 2004].

基因型-表型相关性

基因型-表型 相关性对大多数致病突变是不可获得的. 见 Table 2 (pdf) 可获得更多信息有关于突变 基因 和观察到的纤毛缺陷的相关性. 例如:

• 儿童具有 双等位基因的 致病突变在 CCDC39 或 CCDC40 上(与微管解体和内动力蛋白臂缺陷相关) 其肺功能更差 胸部CT可见更多支气管扩张, 重量更轻比起那些双等位基因致病突变在那些仅和外动力蛋白臂缺陷相关的基因或内外动力蛋白臂缺陷都相关的基因 [Davis et al 2015].
• 个体具有双等位基因的 致病突变在RSPH1 上有更温和的肺病比起同年龄的双等位基因致病突变在与外动力蛋白臂缺陷相关的基因上的个体 [Knowles et al 2014].
• 个体患有PCD有 双等位基因的 致病突变在 CCDC65, DRC1, HYDIN, RSPH1, RSPH4A, 和 RSPH9 上其微结构和正常的相比不够分立/清晰不能分辨.
• 个体有致病突变在编码中央复合体或径向轴条蛋白成分的基因上(比如, RSPH1, RSPH3, RSPH4A, RSPH9, 和 HYDIN)没有内脏位置异常.

命名法

现在称为原发性纤毛不动症（PCD）过去用来描述此病症的名字包括纤毛运动障碍综合症和阿西利亚综合症.

和全内脏反位相关的PCD称为卡塔格内综合症.

流行性

PCD在挪威和日本的群体中发生概率大概为1:16,000 , 此数值推测源于射线照相术的调查和具有支气管扩张临床证据的右位心 [Torgersen 1950, Katsuhara et al 1972]. 基于这些数据, 在美国患有PCD个体的总数约为12,000 到 17,000.在有很多

 近亲婚配的地方病例在人群中发生的概率更高.比如:

• PCD 发生的概率是 1:400 在定居在北荷兰的渔村的福伦丹人中 [Onoufriadis et al 2013].
• 使用纤毛拍频测试, 盛行的PCD 发生概率在南亚人群中为1:2265 (主要祖先是巴基斯坦) 在英国 [O’Callaghan et al 2010].
• 在美国的阿米什人和门诺派教徒中PCD非常盛行 [Ferkol et al 2013].

初步诊断后的评估

为了确定疾病程度评价和确立患有原发性纤毛不动症（PCD）的个体的需要 (PCD), 建议使用以下评估:

• 肺病
  • 呼吸道状况(主要是痰的状况)来确定被感染的组织并指导抗菌治疗. 对年长的儿童和成人针对非结核分支杆菌的特定环境也包括在其中.
  • 胸部x线照片 和/或胸部CT可用来确定呼吸道疾病和支气管扩张的分布位置和严重程度
  • 肺部功能测试 (肺量测定法)来确定阻塞性损伤的严重程度 
  • 脉搏血氧仪,如果达到边缘线也需要隔夜饱和度研究 
• 鼻塞和/或鼻窦炎. 鼻窦成像 (鼻窦x光或最好是鼻窦CT)
• 慢性/反复性耳部感染. 正式的听力评估 (见 Deafness and Hereditary Hearing Loss Overview 可知不同年龄所用的听力评估.)
• 其他. 临床的基因咨询

治疗症状

现在, 没有专门的治疗方案可以治疗纤毛功能不良. 此部分所述的治疗方法是根据经验得来的目的是治疗纤毛和精子鞭毛功能不良的后果. 几乎没有使用PCD专门的治疗方案的材料支持.

肺病. 处治PCD患者应包括积极的措施以提高粘液的清洁度, 预防呼吸道感染, 和治疗细菌感染.增加粘液清洁度的方法和治疗

 囊胞性纤维症的方法相似, 包括胸背叩击和体位引流, 震荡背心, 和呼吸动作以帮助呼吸道远端的清洁. 因为咳嗽是有效的清洁方法, 病人应该被鼓励咳嗽并用其他帮助深呼吸和咳嗽的活动 (比如., 剧烈运动).常规免疫接种可保护免受呼吸道病原体的感染

:

• 百日咳
• b型流感嗜血杆菌
• 肺炎球菌疫苗
• 每年流感病毒疫苗

合适的抗生素疗法治疗呼吸道细菌感染 (支气管炎, 鼻窦炎, 和中耳炎) 是必要的以防止不可逆的损伤. 痰环境可以用来指导选择合适的抗菌疗法. 那些抗生素疗法一疗程完成后症状在几天或几周内反复的患者, 扩大抗生素的使用范围或者甚至要考虑预防性抗生素的范围. (考虑使用慢性抗生素疗法需要评估会产生多药耐药细菌的风险.)对患有局部支气管扩张的个体

, 可使用肺叶切除以减少其余留下来的肺叶的感染.这种方法,然而 ,是有争议的;决策过程也应该包括咨询PCD方面的专家.肺移植使用在肺病末期的患者上

.

鼻塞和鼻窦炎. 在一些有大范围鼻窦炎的患者身上, 鼻窦手术可以帮助改善减缓症状.

慢性/反复性耳部感染. 抗生素疗法无效果的中耳炎, PE管放置法可能会有帮助PE; 然而, 一些PCD患者使用PE管放置法后会有进攻性的耳液溢 [Hadfield et al 1997].语言障碍矫正和助听器对耳聋和语言迟缓的儿童来说可能是需要的

.

男性不育. 一对夫妇中男性有PCD引发的不育可以选择使用ICSI（卵母细胞胞浆内单精子注射）体外授精. 在这个过程中, 精子从精液中获取得到(在少精的男性中)或者从睾丸活检中提取(在阻梗性无精症男性患者中)精子通过体外授精注射到提取的卵子中  [Sha et al 2014].其他的方法是人工授精通过捐献精子

 (AIDS).

器官位置异常. 典型地, 器官位置异常不需要介入除非有生理功能不良 (比如, 先天的 心脏病)需要手术介入 .

预防次级并发症

合适的预防方法:

• 日常免疫接种(包括流感疫苗和肺炎双球菌疫苗)防止呼吸道感染 
• 有关感染控制的教育包括注意洗手,避免和病人接触,正确的清洁/消毒呼吸设备, 和早使用抗生素治疗呼吸疾病(由之前呼吸道状况决定)

监测

接下来需要由肺专家监测肺功能和痰中的病原体并评估肺病的程度/级数.对年幼的患有中耳炎的儿童

, 日常的听力评估是必要的, 并且应该持续到青少年期, 到青少年期听力通常是正常的 [Majithia et al 2005]. 通常, 耳部疾病在童年后期会改善听力筛查不是必须的.

需要避免的药剂/环境

不应该使用止咳药因为咳嗽对分泌物清除很重要.暴露在呼吸道病原体

, 烟草烟雾, 和其他污染物和刺激物可能会损坏呼吸道黏膜并且应该避免刺激粘液分泌.

对有风险亲属评估

应该对 先证者 年长和年幼的同胞评估为了尽早确认那些可以从开始实施治疗和预防措施受益的人.

• 如果家庭中的致病突变是已知的, 使用分子遗传学检测 可以确定有风险的同胞的基因状态.
• 如果家庭中的致病突变不是已知的,严格的临床病例史和身体检查并需要胸片和 鼻一氧化氮测量 来判断有风险同胞的疾病状态.

见 Genetic Counseling 可知有风险同胞的 遗传咨询 信息.

怀孕管理

对患有PCD的女性, 任何肺部感染和肺功能状况应该被PCD（或囊胞性纤维症）专家严格评估来决定孩子所承受的风险.

调查中的治疗方法

查 ClinicalTrials.gov 获取一系列疾病和病症的临床研究相关信息. 注意:不一定有此病的临床试验.

遗传方式

原发性纤毛不动症 (PCD) 以 常染色体隐性遗传 方式遗传.注意

:尽管其他的遗传方式在少数报道中也被提出  [Narayan et al 1994, Badano et al 2006, Moore et al 2006, Bukowy-Bieryłło et al 2013], 常染色体显性遗传 没有被任何随后的出版物报道或者在作者所实验的超过500个参与Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)的病人中被观察到.

家庭成员的风险 — 常染色体隐性遗传

 先证者的父母

• 受累的 个体的父母必然是杂合子 (也就是说, 携带一个PCD-相关 致病性变异).
• 杂合子是无症状的没有患有PCD的风险.

 先证者的同胞

• 理论上, 每个 受累的 个体的同胞有25%的概率是患病的, 有 50% 的概率是无症状的 杂合子 (携带者), 并有 25% 的概率既不患病又不是杂合子.
• 杂合子是无症状的没有患有PCD的风险.

 先证者的后代. 患者的后代必然是杂合子(PCD-相关 致病性变异的携带者).

先证者其他家族成员. 先证者父母的每个同胞有50%的风险是携带一个PCD-相关 致病性变异的 携带者 .

杂合子(携带者)检测

有风险亲属的携带测试需要提前确认家庭中的PCD-相关致病突变.

相关的遗传咨询问题

见 处治, 有风险亲属评估 可获得有风险亲属的评估信息出于早期诊断治疗目的.

计划生育

• 测定基因风险, 确定 携带者 基因状态,并讨论产前诊断是否可行的最优时间是怀孕之前 .
• 应该为 受累的，携带的，或有患病或携带风险的年轻成年人提供 遗传咨询 (包括讨论子代潜在的风险和生殖选择).

DNA银行 是一个储存 DNA (主要是从白细胞中提取的) 以便将来使用. 因为测试方法和我们对基因的理解, 等位基因突变, 和疾病在将来很可能会增多, 应该考虑建设受累的 人群的DNA银行.

产前诊断和植入前遗传 

一旦 受累的 家庭成员的PCD-关联致病突变被确认, 高患病风险的妊娠的产前诊断和PCD 植入前遗传诊断 是可行的.医学专家和家庭内使用产前诊断的观点可能不同, 尤其是如果测试是出于终止妊娠的目的而不是早期诊断的目的. 尽管大多数中心认为决定是否做产前诊断是父母选择, 这些事情的考虑还是合适的.

分子遗传病理

纤毛, 细胞器几乎在所有细胞中存在, 从一个中心粒修饰形成的毛基体中放射出来. 不同种类的纤毛包括: 运动纤毛, 初级静纤毛, 和初级动纤毛 (比如说, 节点纤毛). 纤毛是复杂的, 高度保守的结构. 动纤毛大约由250个蛋白组成; 每个纤毛是 ‘9+2’ 结构有9个外周微管双联体包围中央微管对, 中央微管对也叫做轴丝 (Figure 1). 内外动力蛋白臂在外周微管上在透射电子显微镜纤毛横截面图像上能看到.内外动力蛋白臂组成轴丝中的微管双联体的连接桥梁并是纤毛震动的动力驱动蛋白

 [Afzelius et al 2001, Afzelius 2004, Zariwala et al 2007]. 外动力蛋白臂由几条重链,中间链,和轻链组成 [Satir 1999]. 内动力蛋白臂非常复杂随着轴丝整个长度的不同而不同 [Perrone et al 2000, DiBella & King 2001].动纤毛上的缺陷和原发性纤毛不动症

 (PCD)/卡塔格内综合症有关, 并且在 “初级” (感觉)纤毛上的缺陷和几个人类疾病相关包括 Bardet-Biedl 综合症 (纤毛的基体), 常染色体显性多囊肾病, 常染色体隐性多囊肾病 (肾单纤毛缺陷), 肾结核, Joubert 综合症, 色素性视网膜炎 (光感受器连接纤毛), 脑积水, 和 Alstrom 综合症 [Afzelius 2004, Badano et al 2006, Zariwala et al 2007, Leigh et al 2009, Tobin & Beales 2009]. 那些疾病大多数在基因上是杂合子, 还有很多基因需要确定 [Badano et al 2006, Tobin & Beales 2009].

PCD通过呼吸道纤毛以及精子的鞭毛结构,功能,和生物基因异常来判断. 动力蛋白臂缺少 (或较短) 发生在大约 55% 的有明确的微结构缺损的人中; 大约 10% 的人群有中央复合体或径向轴条或微管连接蛋白缺陷 (在外周微管二联体之间并是动力蛋白调控复合体的一部分对轴丝弯曲很重要). 一些PCD患者 (~30%) 没有明显的微结构缺陷 [Knowles et al 2013a, Davis et al 2015].50%的PCD患者有全内脏反位说明纤毛对胚胎形成左右不对称结构的诱导有重要作用

.点

这可获得生物模型的更多信息.到现在为止

, 32个引起 常染色体隐性遗传 PCD的基因上的致病突变已经被确认 (见 Table A). 很多基因几乎没有致病突变被报道. 通过透射电子显微镜分析受累的 个体的纤毛特征 (见 Table 2), 免疫荧光分析, 和/或 高速视频显微镜分析可以帮助更进一步解释等位基因突变的临床重要性或者分析 意义不确定的突变.注意

: 通常的突变基因的信息 (也就是说, 那些 >1%  PCD的基因突变; 见 Table 1A) 在下方列出来, 按 位点的顺序.点

 这 (pdf) 可获得少发的突变基因的信息 (也就是说, 那些 <1%  PCD的基因突变; 见 Table 1B).

获得基因 总结的信息和以下基因的蛋白的信息, 见 Table A, 基因.

引用文献

• Afzelius BA. Cilia-related diseases. J Pathol. 2004;204:470-7. [PubMed: 15495266]
• Afzelius BA, Mossberg B, Bergstrom SE. Immotile cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Basis of Inherited Disease. New York, NY: McGraw-Hill; 2001:4817-27.
• Alsaadi MM, Erzurumluoglu AM, Rodriguez S, Guthrie PA, Gaunt TR, Omar HZ, Mubarak M, Alharbi KK, Al-Rikabi AC, Day IN. Nonsense mutation in coiled-coil domain containing 151 gene (CCDC151) causes primary ciliary dyskinesia. Hum Mutat. 2014;35:1446-48. [PMC free article: PMC4489323] [PubMed: 25224326]
• Austin-Tse C, Halbritter J, Zariwala MA, Gilberti RM, Gee HY, Hellman N, Pathak N, Liu Y, Panizzi JR, Patel-King RS, Tritschler D, Bower R, O’Toole E, Porath JD, Hurd TW, Chaki M, Diaz KA, Kohl S, Lovric S, Hwang DY, Braun DA, Schueler M, Airik R, Otto EA, Leigh MW, Noone PG, Carson JL, Davis SD, Pittman JE, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Dell SD, Rosenfeld M, Milla CE, Loges NT, Omran H, Porter ME, King SM, Knowles MR, Drummond IA, Hildebrandt F. Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. Am J Hum Genet. 2013;93:672-86. [PMC free article: PMC3791264] [PubMed: 24094744]
• Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-48. [PubMed: 16722803]
• Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N, Rossier C, Jorissen M, Armengot M, Meeks M, Mitchison HM, Chung EM, Delozier-Blanchet CD, Craigen WJ, Antonarakis SE. Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2002;99:10282-6. [PMC free article: PMC124905] [PubMed: 12142464]
• Becker-Heck A, Zohn IE, Okabe N, Pollock A, Lenhart KB, Sullivan-Brown J, McSheene J, Loges NT, Olbrich H, Haeffner K, Fliegauf M, Horvath J, Reinhardt R, Nielsen KG, Marthin JK, Baktai G, Anderson KV, Geisler R, Niswander L, Omran H, Burdine RD. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. 2011;43:79-84. [PMC free article: PMC3132183] [PubMed: 21131974]
• Ben Khelifa M, Coutton C, Zouari R, Karaouzène T, Rendu J, Bidart M, Yassine S, Pierre V, Delaroche J, Hennebicq S, Grunwald D, Escalier D, Pernet-Gallay K, Jouk PS, Thierry-Mieg N, Touré A, Arnoult C, Ray PF. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94:95-104. [PMC free article: PMC3882734] [PubMed: 24360805]
• Blanchon S, Legendre M, Copin B, Duquesnoy P, Montantin G, Kott E, Dastot F, Jeanson L, Cachanado M, Rousseau A, Papon JF, Beydon N, Brouard J, Crestani B, Deschildre A, Désir J, Dollfus H, Leheup B, Tamalet A, Thumerelle C, Vojtek AM, Escalier D, Coste A, de Blic J, Clément A, Escudier E, Amselem S. Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. J Med Genet. 2012;49:410-6. [PubMed: 22693285]
• Boon M, Wallmeier J, Ma L, Loges NT, Jaspers M, Olbrich H, Dougherty GW, Raidt J, Werner C, Amirav I, Hevroni A, Abitbul R, Avital A, Soferman R, Wessels M, O’Callaghan C, Chung EM, Rutman A, Hirst RA, Moya E, Mitchison HM, Van Daele S, De Boeck K, Jorissen M, Kintner C, Cuppens H, Omran H. MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun. 2014;5:4418. [PubMed: 25048963]
• Brown DE, Pittman JE, Leigh MW, Fordham L, Davis SD. Early lung disease in young children with primary ciliary dyskinesia. Pediatr Pulmonol. 2008;43:514-6. [PubMed: 18383332]
• Budny B, Chen W, Omran H, Fliegauf M, Tzschach A, Wisniewska M, Jensen LR, Raynaud M, Shoichet SA, Badura M, Lenzner S, Latos-Bielenska A, Ropers HH. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006;120:171-8. [PubMed: 16783569]
• Bukowy-Bieryłło Z, Ziętkiewicz E, Loges NT, Wittmer M, Geremek M, Olbrich H, Fliegauf M, Voelkel K, Rutkiewicz E, Rutland J, Morgan L, Pogorzelski A, Martin J, Haan E, Berger W, Omran H, Witt M. RPGR mutations might cause reduced orientation of respiratory cilia. Pediatr Pulmonol. 2013;48:352-63. [PubMed: 22888088]
• Casey JP, McGettigan PA, Healy F, Hogg C, Reynolds A, Kennedy BN, Ennis S, Slattery D, Lynch SA. Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population. Eur J Hum Genet. 2015;23:210-7. [PMC free article: PMC4297907] [PubMed: 24824133]
• Castleman VH, Romio L, Chodhari R, Hirst RA, de Castro SC, Parker KA, Ybot-Gonzalez P, Emes RD, Wilson SW, Wallis C, Johnson CA, Herrera RJ, Rutman A, Dixon M, Shoemark A, Bush A, Hogg C, Gardiner RM, Reish O, Greene ND, O’Callaghan C, Purton S, Chung EM, Mitchison HM. Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet. 2009;84:197-209. [PMC free article: PMC2668031] [PubMed: 19200523]
• Chilvers MA, Rutman A, O’Callaghan C. Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol. 2003;112:518-24. [PubMed: 13679810]
• Daniels ML, Leigh MW, Davis SD, Armstrong MC, Carson JL, Hazucha M, Dell SD, Eriksson M, Collins FS, Knowles MR, Zariwala MA. Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat. 2013;34:1352-6. [PMC free article: PMC3906677] [PubMed: 23798057]
• Davis SD, Ferkol TW, Rosenfeld M, Lee H-S, Dell SD, Sagel SD, Milla C, Zariwala MA, Pittman JE, Shapiro AJ, Carson JL, Krischer J, Hazucha MJ, Cooper ML, Knowles MR, Leigh MW. Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med. 2015;191:316-24. [PMC free article: PMC4351577] [PubMed: 25493340]
• DiBella LM, King SM. Dynein motors of the Chlamydomonas flagellum. Int Rev Cytol. 2001;210:227-68. [PubMed: 11580207]
• Diggle CP, Moore DJ, Mali G, zur Lage P, Ait-Lounis A, Schmidts M, Shoemark A, Garcia Munoz A, Halachev MR, Gautier P, Yeyati PL, Bonthron DT, Carr IM, Hayward B, Markham AF, Hope JE, von Kriegsheim A, Mitchison HM, Jackson IJ, Durand B, Reith W, Sheridan E, Jarman AP, Mill P. HEATR2 plays a conserved role in assembly of the ciliary motile apparatus. PLoS Genet. 2014;10:e1004577. [PMC free article: PMC4168999] [PubMed: 25232951]
• Djakow J, Svobodová T, Hrach K, Uhlík J, Cinek O, Pohunek P. Effectiveness of sequencing selected exons of DNAH5 and DNAI1 in diagnosis of primary ciliary dyskinesia. Pediatr Pulmonol. 2012;47:864-75. [PubMed: 22416021]
• Duquesnoy P, Escudier E, Vincensini L, Freshour J, Bridoux AM, Coste A, Deschildre A, de Blic J, Legendre M, Montantin G, Tenreiro H, Vojtek AM, Loussert C, Clément A, Escalier D, Bastin P, Mitchell DR, Amselem S. Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. Am J Hum Genet. 2009;85:890-6. [PMC free article: PMC2790569] [PubMed: 19944405]
• Duriez B, Duquesnoy P, Escudier E, Bridoux AM, Escalier D, Rayet I, Marcos E, Vojtek AM, Bercher JF, Amselem S. A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2007;104:3336-41. [PMC free article: PMC1805560] [PubMed: 17360648]
• Failly M, Bartoloni L, Letourneau A, Munoz A, Falconnet E, Rossier C, De Santi MM, Santamaria F, Sacco O, Delozier-Blanchet CD, Lazor R, Blouin JL. Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. J Med Genet. 2009;46:281-6. [PubMed: 19357118]
• Failly M, Saitta A, Muñoz A, Falconnet E, Rossier C, Santamaria F, de Santi MM, Lazor R, DeLozier-Blanchet CD, Bartoloni L, Blouin JL. DNAI1 mutations explain only 2% of primary ciliary dykinesia. Respiration. 2008;76:198-204. [PubMed: 18434704]
• Ferkol T, Leigh M. Primary ciliary dyskinesia and newborn respiratory distress. Semin Perinatol. 2006;30:335-40. [PubMed: 17142159]
• Ferkol TW, Puffenberger EG, Lie H, Helms C, Strauss KA, Bowcock A, Carson JL, Hazucha M, Morton DH, Patel AC, Leigh MW, Knowles MR, Zariwala MA. Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. J Pediatr. 2013;163:383-7. [PMC free article: PMC3725203] [PubMed: 23477994]
• Hadfield PJ, Rowe-Jones JM, Bush A, Mackay IS. Treatment of otitis media with effusion in children with primary ciliary dyskinesia. Clin Otolaryngol Allied Sci. 1997;22:302-6. [PubMed: 9298603]
• Hjeij R, Lindstrand A, Francis R, Zariwala MA, Liu X, Li Y, Damerla R, Dougherty GW, Abouhamed M, Olbrich H, Loges NT, Pennekamp P, Davis EE, Carvalho CM, Pehlivan D, Werner C, Raidt J, Köhler G, Häffner K, Reyes-Mugica M, Lupski JR, Leigh MW, Rosenfeld M, Morgan LC, Knowles MR, Lo CW, Katsanis N, Omran H. ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. Am J Hum Genet. 2013;93:357-67. [PMC free article: PMC3738828] [PubMed: 23849778]
• Hjeij R, Onoufriadis A, Watson CM, Slagle CE, Klena NT, Dougherty GW, Kurkowiak M, Loges NT, Diggle CP, Morante NF, Gabriel GC, Lemke KL, Li Y, Pennekamp P, Menchen T, Konert F, Marthin JK, Mans DA, Letteboer SJ, Werner C, Burgoyne T, Westermann C, Rutman A, Carr IM, O'Callaghan C, Moya E, Chung EM. UK10K Consortium, Sheridan E, Nielsen KG, Roepman R, Bartscherer K, Burdine RD, Lo CW, Omran H, Mitchison HM. CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation. Am J Hum Genet. 2014;95:257-74. [PMC free article: PMC4157146] [PubMed: 25192045]
• Horani A, Druley TE, Zariwala MA, Patel AC, Levinson BT, Van Arendonk LG, Thornton KC, Giacalone JC, Albee AJ, Wilson KS, Turner EH, Nickerson DA, Shendure J, Bayly PV, Leigh MW, Knowles MR, Brody SL, Dutcher SK, Ferkol TW. Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2012;91:685-93. [PMC free article: PMC3484505] [PubMed: 23040496]
• Hornef N, Olbrich H, Horvath J, Zariwala MA, Fliegauf M, Loges NT, Wildhaber J, Noone PG, Kennedy M, Antonarakis SE, Blouin JL, Bartoloni L, Nusslein T, Ahrens P, Griese M, Kuhl H, Sudbrak R, Knowles MR, Reinhardt R, Omran H. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006;174:120-6. [PMC free article: PMC2662904] [PubMed: 16627867]
• Imtiaz F, Allam R, Ramzan K, Al-Sayed M. Variation in DNAH1 may contribute to primary ciliary dyskinesia. BMC Med Genet. 2015;16:14. [PMC free article: PMC4422061] [PubMed: 25927852]
• Jeanson L, Copin B, Papon JF, Dastot-Le Moal F, Duquesnoy P, Montantin G, Cadranel J, Corvol H, Coste A, Désir J, Souayah A, Kott E, Collot N, Tissier S, Louis B, Tamalet A, de Blic J, Clement A, Escudier E, Amselem S, Legendre M. RSPH3 mutations cause primary ciliary dyskinesia with central-complex and near absence of radial spokes. Am J Hum Genet. 2015;97:153-62. [PMC free article: PMC4571005] [PubMed: 26073779]
• Katsuhara K, Kawamoto S, Wakabayashi T, Belsky JL. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest. 1972;61:56-61. [PubMed: 4538074]
• Kennedy MP, Leigh MW, Dell S, Morgan L, Molina PL, Zariwala M, Minnix S, Noone PG, Knowles MR. Primary ciliary dyskinesia and situs ambiguus/heterotaxy: Organ laterality defects other than situs inversus totalis. Proc Am Thorac Soc. 2006;3:A399.
• Kim RH, A, Hall D, Cutz E, Knowles MR, Nelligan KA, Nykamp K, Zariwala MA, Dell SD. The role of molecular genetic analysis in the diagnosis of primary ciliary dyskinesia. Ann Am Thorac Soc. 2014;11:351-9. [PMC free article: PMC4028737] [PubMed: 24498942]
• Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia: recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013a;188:913-22. [PMC free article: PMC3826280] [PubMed: 23796196]
• Knowles MR, Leigh MW, Carson JL, Davis SD, Dell SD, Ferkol TW, Olivier KN, Sagel SD, Rosenfeld M, Burns KA, Minnix SL, Armstrong MC, Lori A, Hazucha MJ, Loges NT, Olbrich H, Becker-Heck A, Schmidts M, Werner C, Omran H, Zariwala MA. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax. 2012;67:433-41. [PMC free article: PMC3739700] [PubMed: 22184204]
• Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA., Genetic Disorders of Mucociliary Clearance Consortium. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013b;92:99-106. [PMC free article: PMC3542458] [PubMed: 23261302]
• Knowles MR, Ostrowski LE, Leigh MW, Sears PR, Davis SD, Wolf WE, Hazucha MJ, Carson JL, Olivier KN, Sagel SD, Rosenfeld M, Ferkol TW, Dell SD, Milla CE, Randell SH, Yin W, Sannuti A, Metjian HM, Noone PG, Noone PJ, Olson CA, Patrone MV, Dang H, Lee HS, Hurd TW, Gee HY, Otto EA, Halbritter J, Kohl S, Kircher M, Krischer J, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Zariwala MA. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014;189:707-17. [PMC free article: PMC3983840] [PubMed: 24568568]
• Knowles MR, Ostrowski LE, Loges NT, Hurd T, Leigh MW, Huang L, Wolf WE, Carson JL, Hazucha MJ, Yin W, Davis SD, Dell SD, Ferkol TW, Sagel SD, Olivier KN, Jahnke C, Olbrich H, Werner C, Raidt J, Wallmeier J, Pennekamp P, Dougherty GW, Hjeij R, Gee HY, Otto EA, Halbritter J, Chaki M, Diaz KA, Braun DA, Porath JD, Schueler M, Baktai G, Griese M, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Omran H, Zariwala MA. Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013c;93:711-20. [PMC free article: PMC3791252] [PubMed: 24055112]
• Kosaki K, Ikeda K, Miyakoshi K, Ueno M, Kosaki R, Takahashi D, Tanaka M, Torikata C, Yoshimura Y, Takahashi T. Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality. Am J Med Genet A. 2004;129A:308-11. [PubMed: 15326634]
• Kott E, Duquesnoy P, Copin B, Legendre M, Moal FD, Montantin G, Jeanson L, Tamalet A, Papon J, Siffroi J, Rives N, Mitchell V, de Blic J, Coste A, Clement A, Escalier D, Touré A, Escudier E, Amselem S. Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. Am J Hum Genet. 2012;91:958-64. [PMC free article: PMC3487148] [PubMed: 23122589]
• Kott E, Legendre M, Copin B, Papon JF, Dastot-Le Moal F, Montantin G, Duquesnoy P, Piterboth W, Amram D, Bassinet L, Beucher J, Beydon N, Deneuville E, Houdouin V, Journel H, Just J, Nathan N, Tamalet A, Collot N, Jeanson L, Le Gouez M, Vallette B, Vojtek AM, Epaud R, Coste A, Clement A, Housset B, Louis B, Escudier E, Amselem S. Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. Am J Hum Genet. 2013;93:561-70. [PMC free article: PMC3769924] [PubMed: 23993197]
• Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009;11:473-87. [PMC free article: PMC3739704] [PubMed: 19606528]
• Loges NT, Olbrich H, Becker-Heck A, Häffner K, Heer A, Reinhard C, Schmidts M, Kispert A, Zariwala MA, Leigh MW, Knowles MR, Zentgraf H, Seithe H, Nürnberg G, Nürnberg P, Reinhardt R, Omran H. Deletion and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arms defects. Am J Hum Genet. 2009;85:883-9. [PMC free article: PMC2795801] [PubMed: 19944400]
• Loges NT, Olbrich H, Fenske L, Mussaffi H, Horvath J, Fliegauf M, Kuhl H, Baktai G, Peterffy E, Chodhari R, Chung EM, Rutman A, O’Callaghan C, Blau H, Tiszlavicz L, Voelkel K, Witt M, Zietkiewicz E, Neesen J, Reinhardt R, Mitchison HM, Omran H. DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. Am J Hum Genet. 2008;83:547-58. [PMC free article: PMC2668028] [PubMed: 18950741]
• Lucas JS, Leigh MW. Diagnosis of primary ciliary dyskinesia: searching for a gold standard. Eur Respir J. 2014;44:1418-22. [PubMed: 25435529]
• MacCormick J, Robb I, Kovesi T, Carpenter B. Optimal biopsy techniques in the diagnosis of primary ciliary dyskinesia. J Otolaryngol. 2002;31:13-7. [PubMed: 11881766]
• Majithia A, Fong J, Hariri M, Harcourt J. Hearing outcomes in children with primary ciliary dyskinesia--a longitudinal study. Int J Pediatr Otorhinolaryngol. 2005;69:1061-4. [PubMed: 16005347]
• Marthin JK, Petersen N, Skovgaard LT, Nielsen KG. Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. Am J Respir Crit Care Med. 2010;181:1262-8. [PubMed: 20167855]
• Mazor M, Alkrinawi S, Chalifa-Caspi V, Manor E, Sheffield VC, Aviram M, Parvari R. Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet. 2011;88:599-607. [PMC free article: PMC3146731] [PubMed: 21496787]
• Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, Belmont J, Beydon N, Billen F, Clément A, Clercx C, Coste A, Crosbie R, de Blic J, Deleuze S, Duquesnoy P, Escalier D, Escudier E, Fliegauf M, Horvath J, Hill K, Jorissen M, Just J, Kispert A, Lathrop M, Loges NT, Marthin JK, Momozawa Y, Montantin G, Nielsen KG, Olbrich H, Papon JF, Rayet I, Roger G, Schmidts M, Tenreiro H, Towbin JA, Zelenika D, Zentgraf H, Georges M, Lequarré AS, Katsanis N, Omran H, Amselem S. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011;43:72-8. [PMC free article: PMC3509786] [PubMed: 21131972]
• Mitchison HM, Schmidts M, Loges NT, Freshour J, Dritsoula A, Hirst RA, O’Callaghan C, Blau H, Al Dabbagh M, Olbrich H, Beales PL, Yagi T, Mussaffi H, Chung EM, Omran H, Mitchell DR. Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nat Genet. 2012;44:381-9. [PMC free article: PMC3315610] [PubMed: 22387996]
• Moore A, Escudier E, Roger G, Tamalet A, Pelosse B, Marlin S, Clement A, Geremek M, Delaisi B, Bridoux AM, Coste A, Witt M, Duriez B, Amselem S. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet. 2006;43:326-33. [PMC free article: PMC2563225] [PubMed: 16055928]
• Moore DJ, Onoufriadis A, Shoemark A, Simpson MA, zur Lage PI, de Castro SC, Bartoloni L, Gallone G, Petridi S, Woollard WJ, Antony D, Schmidts M, Didonna T, Makrythanasis P, Bevillard J, Mongan NP, Djakow J, Pals G, Lucas JS, Marthin JK, Nielsen KG, Santoni F, Guipponi M, Hogg C, Antonarakis SE, Emes RD, Chung EM, Greene ND, Blouin JL, Jarman AP, Mitchison HM. Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. Am J Hum Genet. 2013;93:346-56. [PMC free article: PMC3738835] [PubMed: 23891471]
• Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S. Primary ciliary dyskinesia and neonatal respiratory distress. Pediatrics. 2014;134:1160-6. [PMC free article: PMC4243067] [PubMed: 25422025]
• Narayan D, Krishnan SN, Upender M, Ravikumar TS, Mahoney MJ, Dolan TF Jr, Teebi AS, Haddad GG. Unusual inheritance of primary ciliary dyskinesia (Kartagener’s syndrome). J Med Genet. 1994;31:493-6. [PMC free article: PMC1049931] [PubMed: 8071978]
• Noone PG, Leigh MW, Sannuti A, Minnix SL, Carson JL, Hazucha M, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med. 2004;169:459-67. [PubMed: 14656747]
• O’Callaghan C, Chetcuti P, Moya E. High prevalence of primary ciliary dyskinesia in a British Asian population. Arch Dis Child. 2010;95:51-52. [PubMed: 19720631]
• Olbrich H, Häffner K, Kispert A, Völkel A, Volz A, Sasmaz G, Reinhardt R, Hennig S, Lehrach H, Konietzko N, Zariwala M, Noone PG, Knowles M, Mitchison HM, Meeks M, Chung EM, Hildebrandt F, Sudbrak R, Omran H. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002;30:143-4. [PubMed: 11788826]
• Olbrich H, Schmidts M, Werner C, Onoufriadis A, Loges NT, Raidt J, Banki NF, Shoemark A, Burgoyne T, Al Turki S, Hurles ME. UK10K Consortium, Köhler G, Schroeder J, Nürnberg G, Nürnberg P, Chung EM, Reinhardt R, Marthin JK, Nielsen KG, Mitchison HM, Omran H. Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Am J Hum Genet. 2012;91:672-84. [PMC free article: PMC3484652] [PubMed: 23022101]
• Omran H, Kobayashi D, Olbrich H, Tsukahara T, Loges NT, Hagiwara H, Zhang Q, Leblond G, O’Toole E, Hara C, Mizuno H, Kawano H, Fliegauf M, Yagi T, Koshida S, Miyawaki A, Zentgraf H, Seithe H, Reinhardt R, Watanabe Y, Kamiya R, Mitchell DR, Takeda H. Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature. 2008;456:611-6. [PMC free article: PMC3279746] [PubMed: 19052621]
• Onoufriadis A, Paff T, Antony D, Shoemark A, Micha D, Kuyt B, Schmidts M, Petridi S, Dankert-Roelse JE, Haarman EG, Daniels JM, Emes RD, Wilson R, Hogg C, Scambler PJ, Chung EM. UK10K, Pals G, Mitchison HM. Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet. 2013;92:88-98. [PMC free article: PMC3542455] [PubMed: 23261303]
• Panizzi JR, Becker-Heck A, Castleman VH, Al-Mutairi DA, Liu Y, Loges NT, Pathak N, Austin-Tse C, Sheridan E, Schmidts M, Olbrich H, Werner C, Häffner K, Hellman N, Chodhari R, Gupta A, Kramer-Zucker A, Olale F, Burdine RD, Schier AF, O’Callaghan C, Chung EM, Reinhardt R, Mitchison HM, King SM, Omran H, Drummond IA. CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet. 2012;44:714-9. [PMC free article: PMC3371652] [PubMed: 22581229]
• Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, Roger G, Clement A, Goossens M, Amselem S, Duriez B. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet. 1999;65:1508-19. [PMC free article: PMC1288361] [PubMed: 10577904]
• Perrone CA, Myster SH, Bower R, O’Toole ET, Porter ME. Insights into the structural organization of the I1 inner arm dynein from a domain analysis of the 1beta dynein heavy chain. Mol Biol Cell. 2000;11:2297-313. [PMC free article: PMC14920] [PubMed: 10888669]
• Satir P. The cilium as a biological nanomachine. FASEB J. 1999;13 Suppl 2:S235-7. [PubMed: 10619134]
• Schwabe GC, Hoffmann K, Loges NT, Birker D, Rossier C, de Santi MM, Olbrich H, Fliegauf M, Failly M, Liebers U, Collura M, Gaedicke G, Mundlos S, Wahn U, Blouin JL, Niggemann B, Omran H, Antonarakis SE, Bartoloni L. Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Hum Mutat. 2008;29:289-98. [PubMed: 18022865]
• Sha YW, Ding L, Li P. Management of primary ciliary dyskinesia/Kartagener’s syndrome in infertile male patients and current progress in defining the underlying genetic mechanism. Asian J Androl. 2014;16:101-6. [PMC free article: PMC3901865] [PubMed: 24369140]
• Shapiro AJ, Davis SD, Ferkol TF, Dell SD, Rosenfeld M, Olivier KN, Sagel SD, Milla C, Zariwala MA, Wolf W, Carson JL, Hazucha MJ, Burns K, Robinson B, Knowles MR, Leigh MW. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: Insights into situs ambiguus and heterotaxy. Chest. 2014a;146:1176-86. [PMC free article: PMC4219335] [PubMed: 24577564]
• Shapiro AJ, Weck KE, Chao KC, Rosenfeld M, Nygren AO, Knowles MR, Leigh MW, Zariwala MA. Cri du chat syndrome and primary ciliary dyskinesia: a common genetic cause on chromosome 5p. J Pediatr. 2014b;165:858-61. [PMC free article: PMC4177261] [PubMed: 25066065]
• Tarkar A, Loges NT, Slagle CE, Francis R, Dougherty GW, Tamayo JV, Shook B, Cantino M, Schwartz D, Jahnke C, Olbrich H, Werner C, Raidt J, Pennekamp P, Abouhamed M, Hjeij R, Köhler G, Griese M, Li Y, Lemke K, Klena N, Liu X, Gabriel G, Tobita K, Jaspers M, Morgan LC, Shapiro AJ, Letteboer SJ, Mans DA, Carson JL, Leigh MW, Wolf WE, Chen S, Lucas JS, Onoufriadis A, Plagnol V, Schmidts M, Boldt K. UK10K, Roepman R, Zariwala MA, Lo CW, Mitchison HM, Knowles MR, Burdine RD, Loturco JJ, Omran H. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet. 2013;45:995-1003. [PMC free article: PMC4000444] [PubMed: 23872636]
• Tobin JL, Beales PL. The nonmotile ciliopathies. Genet Med. 2009;11:386-402. [PubMed: 19421068]
• Torgersen J. Situs inversus, asymmetry, and twinning. Am J Hum Genet. 1950;2:361-70. [PMC free article: PMC1716380] [PubMed: 14837905]
• Wallmeier J, Al-Mutairi DA, Chen CT, Loges NT, Pennekamp P, Menchen T, Ma L, Shamseldin HE, Olbrich H, Dougherty GW, Werner C, Alsabah BH, Köhler G, Jaspers M, Boon M, Griese M, Schmitt-Grohé S, Zimmermann T, Koerner-Rettberg C, Horak E, Kintner C, Alkuraya FS, Omran H. Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet. 2014;46:646-51. [PubMed: 24747639]
• Watson CM, Crinnion LA, Morgan JE, Harrison SM, Diggle CP, Adlard J, Lindsay HA, Camm N, Charlton R, Sheridan E, Bonthron DT, Taylor GR, Carr IM. Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. Hum Mutat. 2014;35:434-41. [PMC free article: PMC4285299] [PubMed: 24307375]
• Wessels MW, den Hollander NS, Willems PJ. Mild fetal cerebral ventriculomegaly as a prenatal sonographic marker for Kartagener syndrome. Prenat Diagn. 2003;23:239-42. [PubMed: 12627427]
• Wirschell M, Olbrich H, Werner C, Tritschler D, Bower R, Sale WS, Loges NT, Pennekamp P, Lindberg S, Stenram U, Carlén B, Horak E, Köhler G, Nürnberg P, Nürnberg G, Porter ME, Omran H. The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nature Genet. 2013;45:262-68. [PMC free article: PMC3818796] [PubMed: 23354437]
• Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, Hjeij R, Dell SD, Chaki M, Dougherty GW, Adan M, Spear PC, Esteve-Rudd J, Loges NT, Rosenfeld M, Diaz KA, Olbrich H, Wolf WE, Sheridan E, Batten TF, Halbritter J, Porath JD, Kohl S, Lovric S, Hwang DY, Pittman JE, Burns KA, Ferkol TW, Sagel SD, Olivier KN, Morgan LC, Werner C, Raidt J, Pennekamp P, Sun Z, Zhou W, Airik R, Natarajan S, Allen SJ, Amirav I, Wieczorek D, Landwehr K, Nielsen K, Schwerk N, Sertic J, Köhler G, Washburn J, Levy S, Fan S, Koerner-Rettberg C, Amselem S, Williams DS, Mitchell BJ, Drummond IA, Otto EA, Omran H, Knowles MR, Hildebrandt F. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet. 2013;93:336-45. [PMC free article: PMC3738827] [PubMed: 23891469]
• Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol. 2007;69:423-50. [PubMed: 17059358]
• Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, Omran H, Amselem S, Knowles MR. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med. 2006;174:858-66. [PMC free article: PMC2648054] [PubMed: 16858015]
• Zhu L, Belmont JW, Ware SM. Genetics of human heterotaxias. Eur J Hum Genet. 2006;14:17-25. [PubMed: 16251896]
• Ziętkiewicz E, Bukowy-Bieryłło Z, Voelkel K, Klimek B, Dmeńska H, Pogorzelski A, Sulikowska-Rowińska A, Rutkiewicz E, Witt M. Mutations in radial spoke head genes and ultrastructural cilia defects in East-European cohort of primary ciliary dyskinesia patients. PLoS One. 2012;7:e33667. [PMC free article: PMC3308995] [PubMed: 22448264]

建议阅读

• Afzelius BA, Mossberg B, Bergström SE. Immotile cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 187. McGraw-Hill. Available online.
• Berdon WE, Willi U. Situs inversus, bronchiectasis, and sinusitis and its relation to immotile cilia: history of the diseases and their discoverers-Manes Kartagener and Bjorn Afzelius. Pediatr Radiol. 2004;34:38-42. [PubMed: 14551758]
• Boon M, Vermeulen FL, Gysemans W, Proesmans M, Jorissen M, De Boeck K. Lung structure-function correlation in patients with primary ciliary dyskinesia. Thorax. 2015;70:339-45. [PubMed: 25673230]
• Eley L, Yates LM, Goodship JA. Cilia and disease. Curr Opin Genet Dev. 2005;15:308-14. [PubMed: 15917207]
• Funkhouser WK 3rd, Niethammer M, Carson JL, Burns KA, Knowles MR, Leigh MW, Zariwala MA, Funkhouser WK Jr. A new tool improves diagnostic test performance for transmission em evaluation of axonemal dynein arms. Ultrastruct Pathol. 2014;38:248-55. [PMC free article: PMC3990650] [PubMed: 23957500]
• Gerdes JM, Katsanis N. Microtubule transport defects in neurological and ciliary disease. Cell Mol Life Sci. 2005;62:1556-70. [PubMed: 15924265]
• Horani A, Brody SL, Ferkol TW. Picking up speed: advances in the genetics of primary ciliary dyskinesia. Pediatr Res. 2014;75:158-64. [PMC free article: PMC3946436] [PubMed: 24192704]
• Hosie P, Fitzgerald DA, Jaffe A, Birman CS, Morgan L. Primary ciliary dyskinesia: overlooked and undertreated in children. J Paediatr Child Health. 2014;50:952-8. [PubMed: 24943508]
• Hosie PH, Fitzgerald DA, Jaffe A, Birman CS, Rutland J, Morgan LC. Presentation of primary ciliary dyskinesia in children: 30 years’ experience. J Paediatr Child Health. 2015;51:722-6. [PubMed: 25510893]
• Kennedy MP, Noone PG, Carson J, Molina PL, Ghio A, Zariwala MA, Minnix SL, Knowles MR. Calcium stone lithoptysis in primary ciliary dyskinesia. Respir Med. 2007;101:76-83. [PubMed: 16757159]
• Leigh MW, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: improving the diagnostic approach. Curr Opin Pediatr. 2009;21:320-5. [PMC free article: PMC3665363] [PubMed: 19300264]
• Lobo J, Zariwala MA, Noone PG. Primary ciliary dyskinesia. Semin Respir Crit Care Med. 2015;36:169-79. [PMC free article: PMC4873960] [PubMed: 25826585]
• Lucas JS, Burgess A, Mitchison HM, Moya E, Williamson M, Hogg C, National PCD. Service, UK. Diagnosis and management of primary ciliary dyskinesia. Arch Dis Child. 2014;99:850-6. [PMC free article: PMC4145427] [PubMed: 24771309]
• Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, Yagi H, Khalifa O, Kureshi S, Chatterjee B, Sabol SL, Swisher M, Connelly PS, Daniels MP, Srinivasan A, Kuehl K, Kravitz N, Burns K, Sami I, Omran H, Barmada M, Olivier K, Chawla KK, Leigh M, Jonas R, Knowles M, Leatherbury L, Lo CW. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125:2232-42. [PMC free article: PMC3770728] [PubMed: 22499950]
• Noone PG, Zariwala M, Knowles MR. Primary ciliary dyskinesia. In: MS Runge, C Patterson, eds. Principles of Molecular Medicine. Totowa, New Jersey: Humana Press; 2006:239-50.
• Omran H, Haffner K, Volkel A, Kuehr J, Ketelsen UP, Ross UH, Konietzko N, Wienker T, Brandis M, Hildebrandt F. Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene. Am J Respir Cell Mol Biol. 2000;23:696-702. [PubMed: 11062149]
• Popatia R, Haver K, Casey A. Primary ciliary dyskinesia: an update on new diagnostic modalities and review of the literature. Pediatr Allergy Immunol Pulmonol. 2014;27:51-9. [PMC free article: PMC4062113] [PubMed: 24963453]
• Quinlan RJ, Tobin JL, Beales PL. Modeling ciliopathies: Primary cilia in development and disease. Curr Top Dev Biol. 2008;84:249-310. [PubMed: 19186246]
• Shapiro AJ, Tolleson-Rinehart S, Zariwala MA, Knowles MR, Leigh MW. The prevalence of clinical features associated with primary ciliary dyskinesia in a heterotaxy population: results of a web-based survey. Cardiol Young. 2015;25:752-9. [PMC free article: PMC4369774] [PubMed: 24905662]
• Werner C, Onnebrink JG, Omran H. Diagnosis and management of primary ciliary dyskinesia. Cilia. 2015;4:2. [PMC free article: PMC4300728] [PubMed: 25610612]
• Ziętkiewicz E, Nitka B, Voelkel K, Skrzypczak U, Bukowy Z, Rutkiewicz E, Humińska K, Przystałowska H, Pogorzelski A, Witt M. Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD). Respir Res. 2010;11:174. [PMC free article: PMC3014902] [PubMed: 21143860]

作者注释

网站:
UNC - Department of Pathology and Laboratory Medicine
UNC - Pulmonary Diseases and Critical Care Medicine - PCD
UNC - Department of Pediatrics

感谢

我们非常感谢所有参与的患者和他们的家庭，感谢US PCD基金会，感谢Dr. Johnny Carson为本节作图。
 

此研究获得下列基金的资助：

• NIH/ORD/NCRR U54 HL096458
• NIH/NHLBI 1 R01 HL071798
• NHLBI/NIH 5 R01 HL117836

本章节的内容由参与的作者负责，并不一定代表NIH的官方观点。

修订历史

• 2015.9.3 (me) 全面更新
•  2013.2.28 (cd)更新：DNAAF3、CCDC103和LRRC6基因的突变检测已经用于临床；HYDIN 和 HEATR2 基因与PCD相关
•  2012.6.7 (cd) 更新：命名改变：TXNDC3 →NME8；已经载入 Molecular Genetics
• 2012.3.8 (cd) 更新：报道DNAAF1 的部分或全基因外显子 缺失和DNAH5基因外显子缺失
• 2012.1.12 (cd)更新：原发性纤毛运动障碍的多基因的检测包已被公布在GeneTests™实验室目录之中2011.11.10 (cd)更新：DNAL1基因的 序列分析和产前检测已用于临床
• 2011.9.15 (me) 全面更新
• 2009.10.6 (me) 全面更新
• 2008.2.1 (cd) 更新： 靶性性突变分析 (检测包，包含DNAI1 和 DNAH5基因61个突变等位基因)和 产前诊断 开始临床应用
• 2007.6.13 (cd) 更新：DNAI1和DNAH5基因飞某些外显子的序列分析可以用于临床
• 2007.1.24 (me) 更新，添加网址
• 2006.7.19 (mbz) 初版上传