Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes
A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A
components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies,
including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner
syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the
IFT-B module, with the exception of IFT80, have unknown roles in human disease. To
identify additional IFT-B components defective in ciliopathies, we independently performed
different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes
in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing
in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding
gene IFT172 in 12 families. All affected individuals displayed abnormalities of the
thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent
with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia
characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts
from affected individuals showed disturbed ciliary composition, suggesting alteration
of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated
the human phenotype and demonstrated a genetic interaction between ift172 and ift80.
In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS.
Our findings link the group of skeletal ciliopathies to an additional IFT-B component,
IFT172, similar to what has been shown for IFT-A.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.