Waters, AM; (2013) Genetic and functional dissection of ciliary genes. Doctoral thesis , UCL (University College London).

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Abstract

Ciliopathy disorders are associated with either abnormal formation or function of cilia. Mutations have been described in over 60 ciliary genes to date. With the identification of over 1,000 ciliary polypeptides, other disorders exhibiting ciliopathy features could result from mutations in other ciliary genes. A new ciliopathy disease gene, CENPF, has been identified in a kindred exhibiting midgestation lethality with congenital malformations suggestive of a novel ciliopathy phenotype. Where conventional approaches such as genome-wide linkage analysis and homozygosity mapping had failed, whole exome capture coupled with massive parallel deep sequencing was successful in elucidating the genetic cause in a single affected case. Identification of compound heterozygous mutations in the causative gene was facilitated through analysis of an unfiltered approach for depth of coverage. Utilising a combinatorial approach of comparative genomics and proteomics, a novel ciliogenic role for the causative gene was identified and proposed by modelling cenpf loss of function in D. rerio and supported by interactions found with I ft 88 and Kif3b, key regulators of ciliogenesis. These data support emerging vidence for the existence of acytoplasmic dynein 1-dependent multiprotein complex which has dual roles in mitosis and ciliogenesis.

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