Spiden, Sarah Louise; (2002) Molecular characterisation of the primary ciliary dyskinesia locus CILD2. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive disorder that results from dysmotility of cilia throughout the body. Affected individuals suffer from recurrent respiratory infections, subfertility and laterality defects affecting left-right axis determination. Three dynein genes encoding ciliary structural components have been shown to be mutated in a small number of PCD patients. The aim of this work was to identify the gene underlying PCD in a group of families of Indian and Arabic origin with a specific ciliary defect, an absence of the axonemal outer dynein arms. This is the most common and clinically significant defect identified in PCD. A novel PCD locus, CILD2, was identified on chromosome 19ql3.4 using the approach of homozygosity mapping in a set of consanguineous pedigrees. A 1.3 Mb candidate interval was initially defined between D19S180-D19S218, with a maximum multipoint lod score of 4.7 at D19S214 (a=0.77). This was narrowed to a region of 650Kb (D19S210-UCL7228.1) by additional microsatellite typing. Within the 650Kb candidate interval, a 280Kb region of homozygosity was identified (D19S254-UCL30217), which contained a region of putative linkage disequilibrium and the marker D19S214. A complete transcript map of the D19S254-UCL30217 interval was constructed, using a combination of practical experiments and bioinformatic analysis involving genomic databases and gene prediction algorithms. The D19S254-UCL30217 critical interval contained 12 known genes, ten of which belonged to a zinc finger-associated gene cluster. DNA sequence analysis of the coding regions of two zinc finger genes did not identify any disease-related mutations, however eight remain to be sequenced in patients. The available coding sequence for the two unique genes in the D19S254-UCL30217 critical region was also screened in PCD patients, however no mutations were detected. One of these novel transcripts was expressed in ciliated tissues and work is still ongoing to confirm the full-length transcript. The absence of any known ciliary gene in the candidate interval suggests that the CILD2 gene encodes a gene of novel ciliary function involved in the structure and function of the axoneme.

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