Investigation of the Possible Role of a Novel Gene, DPCD, in Primary Ciliary Dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by mutations that affect the proper function of cilia. Recently, deletion of DNA polymerase lambda (Poll) in mice produced a phenotype characteristic of PCD (Kobayashi et al., 2002, Mol. Cell. Biol. 22:2769-2776). Because it is unclear how a mutation in a DNA polymerase would result in a specific defect in axonemes, the targeting construct was examined further. Analysis of the genomic region surrounding the Poll gene revealed an uncharacterized gene, named Dpcd, that is predicted to be transcribed from the opposite strand relative to Poll. The deletion of Poll would also remove the first exon of Dpcd. Because it is possible that the PCD phenotype observed is due to the absence of either gene, the expression of these genes during ciliogenesis of human airway epithelial cells was examined. Northern analysis demonstrated that DPCD expression increases during ciliated cell differentiation; the expression of POLL decreases. To examine directly whether DPCD is mutated in cases of human PCD, the complete coding sequence of DPCD was sequenced from 51 unrelated PCD patients. No disease-causing mutations were confirmed; however, one variant could not be excluded. Therefore, DPCD remains a novel candidate gene for PCD.

Acetylproteomic Analysis Reveals Functional Implications of Lysine Acetylation in Human Spermatozoa (sperm)

“…All the acetyl proteins related to sperm motility highlighted by the previous study (31) except DPCD were identified in both studies (Table II), indicating that a minor difference between capacitated and uncapacitated human sperm in terms of protein types might exist, although capacitated sperm were apparently different from uncapacitated sperm in motility. However, because DPCD appeared to be a novel candidate for primary ciliary dyskinesia (38) and Dpcd/ Poll(Ϫ/Ϫ) mice had deficient ciliary motility (39), DPCD acetylation might be a key event in the process of sperm capacitation and ciliary motility that is worth further investigation in the future. Besides, of the four acetyl proteins that might be involved in fusion of sperm-egg plasma (31), only ROPN1B was identified in the present study (Table II), which implied that there are dramatic changes after capacitation in terms of lysine acetylation of these proteins.…”

New insights into the biogenesis of nuclear RNA polymerases?This paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

“…Deletion of RP11-529I10.4/DPCD in mice results in a phenotype similar to primary ciliary dyskinesia (PCD) (Zariwala et al 2004). PCD is a genetic disorder characterized by a defect in axonemal structure resulting in hindrance of normal ciliated and flagellar cells, most notably of the respiratory tract.…”

Mutations ofDNAI1in Primary Ciliary Dyskinesia

“…Nasal nitric oxide (NO) was measured as described previously (3,26). Blood or buccal cells were obtained from the proband (and relatives when possible) for DNA extraction (3,26,38). Genomic DNA was obtained from 106 patients with PCD (90 families) from diverse geographical locations, including Germany (n ϭ 28), France (n ϭ 23), United Kingdom (n ϭ 18), Australia (n ϭ 11), Italy (n ϭ 6), Israel (n ϭ 2), Pakistan (n ϭ 1), and the United States (n ϭ 1).…”