Cystic Fibrosis, Primary Ciliary Dyskinesia, and Diffuse Panbronchiolitis: Hereditary and Non-hereditary—What Are the Roles of Genetic Factors in the Pathogenesis of These Diseases?

  • Masaharu Shinkai
Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)


Cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and diffuse panbronchiolitis (DPB) are rare airway diseases. CF is the most common life-shortening genetic disorder in Caucasians, caused by mutations in a single gene on the long arm of chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). The predominant CFTR mutation is Phe508del, yet more than 2000 variants in this gene have been identified, which can be divided into six classes. Class II mutations, including Phe508del, cause retention of a misfolded protein in the endoplasmic reticulum and subsequent degradation in the proteasome. Patients with Class I, II, and III mutations, which are associated with loss of CFTR function, typically have a severe phenotype, whereas individuals with Class IV, V, and VI mutations, which retain residual CFTR function, have mild lung phenotypes and pancreatic sufficiency. PCD is usually inherited in an autosomal recessive manner and is genetically heterogeneous. Of the 30 mutations that are known to cause PCD, those affecting the DNAH5, DNAI1, DNAAF1 (LRRC50), LRRC6, CCDC39, CCDC40, and DNAH11 genes are found in 15–21%, 2–9%, 4–5%, 3%, 2–10%, 2–8%, and 6% of patients, respectively. In terms of the relationship between phenotype and genotype, mutation of DNAH5, DNAI1, DNAI2, DNAL1, CCDC114, TXNDC3 (NME8), or ARMC4 results in loss of the outer dynein arms. In regard to DPB, an interaction of environmental and genetic factors is thought to underpin the disease. The most probable location for DPB susceptibility genes is thought to lie in a 200 kb major histocompatibility complex (MHC) class I region between HLA-A and HLA-B. This contains the DPB critical region 1 gene (DPCR1, chromosome 6p21.33), as well as MUC21, and the panbronchiolitis-related mucin-like genes 1 and 2 (PBMUCL1 and PBMCL2). The fact that DPCR1, MUC21, PBMUCL1, and PBMUCL2 are all mucin or mucin-like genes is highly relevant for the excessive airway mucus secretion that is typical in DPB. In summary, CF and PCD are both hereditary disorders of mucociliary clearance that result in chronic upper and lower airways disease, while in DPB, it is thought that genetic factors may determine disease susceptibility.


Cystic fibrosis Phe508del Primary ciliary dyskinesia DNAH5 Diffuse panbronchiolitis PBMUCL Hereditary Genetic factor 


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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Masaharu Shinkai
    • 1
  1. 1.Tokyo Shinagawa HospitalTokyoJapan

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