Primary Ciliary Dyskinesia: A search for the responsible genes through linkage and candidate gene approaches

Abstract

Primary Ciliary Dyskinesia (PCD) is an autosomal recessive disorder in which dysmotility to immobility of cilia and flagella result in upper respiratory tract infections, bronchiectasis and male sub-fertility. About half of patients have situs inversus (Kartagener syndrome). Extensive genetic heterogeneity is expected given the complex ultrastructure of cilia and flagella. Recently, the first report of mutations in a specific gene (DNAI1) were reported in a single Kartagener patient (Pennarun et al., AM J HUM GENET 65 suppl, A35, 1999). In Switzerland and as part of a European consortium, we collected DNA samples from 61 families, 31 of which had two or more affected members. A genome-wide linkage search was performed using 188 evenly-spaced microsatellites. Linkage analysis was performed in all families with two affecteds, and in sub-sets of families with situs inversus and with dynein arm deficiency. Data was analyzed using both parametric and non-parametric methods. Although no marker showed statistically-significant values for linkage, several chromosomal regions (4q, 5p, 8p, 16p, and 19q) were identified with suggestive scores. These findings support the hypothesis that mutations in several distinct genes may produce the PCD/ Kartagener phenotypes. As dyneins are good candidates for this disorder, we are currently screening PCD patients for mutations in dynein-related genes mapping to the pinpointed chromosomal regions. Supported by the Swiss OFES (950458) and the Milena Carvajal Foundation, Geneva.