Genetics and biology of primary ciliary dyskinesia

Abstract

Summary Ciliopathies are a growing class of disorders caused by abnormal ciliary axonemal structure and function. Our understanding of the complex genetic and functional phenotypes of these conditions has rapidly progressed. Primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. However, unlike many Mendelian genetic disorders, PCD is not caused by mutations in a single gene or locus, but rather, autosomal recessive mutation in one of many genes that lead to a similar phenotype. The first reported PCD mutations, more than a decade ago, identified genes encoding known structural components of the ciliary axoneme. In recent years, mutations in genes encoding novel cytoplasmic and regulatory proteins have been discovered. These findings have provided new insights into the functions of the motile cilia, and a better understanding of motile cilia disease. Advances in genetic tools will soon allow more precise genetic testing, mandating that clinicians must understand the genetic basis of PCD. Here, we review genetic mutations, their biological impact on cilia structure and function, and the implication of emerging genetic diagnostic tools.

Primary Ciliary Dyskinesia

“…For adults, all males with abnormal spermatozoal movement should be evaluated for PCD, if they have respiratory symptoms. Several medical disorders and phenotypes may coexist with PCD, including complex congenital heart disease, laterality defects, retinitis pigmentosa, hydrocephalus, pectus excavatum, and scoliosis (1-4). …”

“…Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia associated with respiratory distress in term neonates, chronic oto-sino-pulmonary disease, male infertility, and organ laterality defects in ~50% of cases (1-4). This syndrome was initially recognized based on the triad of chronic sinusitis, bronchiectasis, and situs inversus (Kartagener syndrome) (5) and Afzelius later recognized that these patients had “immotile” cilia and defective ciliary ultrastructure (6).…”

“…Further, many physicians do not appreciate and recognize the key clinical features, particularly in infants and children; however, recent advances in defining the clinical phenotype are likely to increase the level of awareness for PCD (10, 11). Moreover, better definition of genotype/phenotype will also facilitate recognition of the early onset and severity of clinical disease in children with PCD (2, 4, 11, 12). …”

“…This article provides an overview of the rapidly evolving state-of-the-art for PCD, including a focus on the diagnosis and treatment of PCD, and a summary of the progress that promises to revolutionize the identification and treatment of patients with PCD (1-4, 11-15). …”

BAR Domain-Containing FAM92 Proteins Interact with Chibby1 To Facilitate Ciliogenesis

“…On the other hand, defects in multicilia are most prominently associated with primary ciliary dyskinesia (PCD). PCD patients typically display chronic respiratory infections, infertility, and hydrocephalus (4).…”