Institut National de la Santé et de la Recherche Médicale UMR_S933, Université Pierre et Marie Curie - Paris 6, and Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Service de Génétique et d'Embryologie Médicales, Paris, France.
J Med Genet. 2012 Jun;49(6):410-6. doi: 10.1136/jmedgenet-2012-100867.
CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described.
All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella.
Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones.
CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.
最近，CCDC39 和 CCDC40 基因被发现与原发性纤毛运动障碍（PCD）有关，这些基因的突变会导致内动力蛋白臂（IDA）缺陷和轴丝结构紊乱；然而，其导致疾病的具体机制尚不清楚。本研究旨在明确 CCDC39/CCDC40 基因突变谱及其相关表型，为此对一组 IDA 缺陷患者进行了大样本筛查，这些患者的临床和纤毛表型均得到了准确描述。
对 40 个无关家系的 43 名患者的 CCDC39 和 CCDC40 外显子和内含子边界进行了测序。本研究记录并比较了临床特征（性别、来源、近亲婚配、侧别缺陷、首发症状和表型评估年龄、新生儿呼吸窘迫、气道感染、鼻息肉、中耳炎、支气管扩张、不孕）、纤毛摆动频率以及纤毛和精子鞭毛的定量超微结构分析。
在 34 个 IDA 缺陷相关轴丝结构紊乱的家系（22 个家系中有 CCDC39 突变，8 个家系中有 CCDC40 突变）中发现了 CCDC39 或 CCDC40 的双等位基因突变。在 28 个已鉴定的突变中，有 14 个是新的突变。在 6 个仅有 IDA 缺陷的家系中未发现突变。具有鉴定突变的患者具有相似的表型，无论是在临床特征还是纤毛结构和功能方面。在 4 名不育男性的精子鞭毛超微结构分析中，发现了与纤毛异常相似的证据。
CCDC39 和 CCDC40 突变是 IDA 缺陷和轴丝结构紊乱的 PCD 的主要原因。携带 CCDC39 或 CCDC40 突变的患者在表型上无法区分。即使临床或纤毛表型无法确定分析优先级，对选定患者进行 CCDC39 和 CCDC40 分析也能以高概率发现突变。
