Cranioectodermal Dysplasia, Sensenbrenner Syndrome, Is a Ciliopathy Caused by Mutations in the IFT122 Gene

Abstract

Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.

Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice

“…Our findings, combined with the fact that proteins mutated in Bardet-Biedl syndrome (40), Jeune syndrome (41), retinitis pigmentosa (42), or Sensenbrenner syndrome (43,44) localize to or constitute IFT particles, strongly suggest that loss of IFT causes photoreceptor degeneration in these diseases as well. On a systemic level, these diseases are connected through a joint network of protein interactions perturbed as a consequence of mutation.…”

Cilia in vertebrate development and disease

“…Over the next ten years, we are likely to witness more disease states associated with dysfunctional cilia (Baker and Beales, 2009; Gilissen et al, 2010;Walczak-Sztulpa et al, 2010), providing additional avenues by which to link developmental processes to disease pathology. Given the diversity of cilia and the unique composition of protein complexes at the transition zone in different tissue types (Garcia-Gonzalo et al, 2011), the spatiotemporal and genetic context-dependent functions of cilia will need to be examined.…”

Subunit Interactions and Organization of the Chlamydomonas reinhardtii Intraflagellar Transport Complex A Proteins

“…IFT A and Human Ciliopathies-Genes encoding five of the six IFT A proteins have recently been associated with human ciliopathies where many of the disease-causing mutations result in single amino acid substitutions or small deletions in IFT43, IFT121, IFT122, IFT139, or IFT144 (82)(83)(84)(85)(86). A complete loss of an IFT A subunit, such as that observed with a murine IFT122 knock-out strain shows that the loss of the IFT A complex is likely to be embryonic lethal in humans (49,87).…”