TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.

TitleTTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.
Publication TypeJournal Article
Year of Publication2011
AuthorsDavis, EE, Zhang, Q, Liu, Q, Diplas, BH, Davey, LM, Hartley, J, Stoetzel, C, Szymanska, K, Ramaswami, G, Logan, CV, Muzny, DM, Young, AC, Wheeler, DA, Cruz, P, Morgan, M, Lewis, LR, Cherukuri, P, Maskeri, B, Hansen, NF, Mullikin, JC, Blakesley, RW, Bouffard, GG, Gyapay, G, Rieger, S, Tönshoff, B, Kern, I, Soliman, NA, Neuhaus, TJ, Swoboda, KJ, Kayserili, H, Gallagher, TE, Lewis, RA, Bergmann, C, Otto, EA, Saunier, S, Scambler, PJ, Beales, PL, Gleeson, JG, Maher, ER, Attié-Bitach, T, Dollfus, H, Johnson, CA, Green, ED, Gibbs, RA, Hildebrandt, F, Pierce, EA, Katsanis, N
Corporate Authors
JournalNat Genet
Volume43
Issue3
Pagination189-96
Date Published2011 Mar
ISSN1546-1718
KeywordsAdaptor Proteins, Signal Transducing, Alleles, Animals, Ciliary Motility Disorders, Genetic Variation, Humans, Mice, Mutation, Pedigree, Photoreceptor Cells, Zebrafish
Abstract

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.

DOI10.1038/ng.756
Alternate JournalNat. Genet.
PubMed ID21258341
PubMed Central IDPMC3071301
Grant ListR01DK064614 / DK / NIDDK NIH HHS / United States
G9901217 / / Medical Research Council / United Kingdom
G0700073 / / Medical Research Council / United Kingdom
R01 DK072301 / DK / NIDDK NIH HHS / United States
R01DK068306 / DK / NIDDK NIH HHS / United States
/ / Medical Research Council / United Kingdom
F32 DK079541-04 / DK / NIDDK NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
G0601347 / / Medical Research Council / United Kingdom
/ / Intramural NIH HHS / United States
R01DK069274 / DK / NIDDK NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
R01 EY012910 / EY / NEI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01EY12910 / EY / NEI NIH HHS / United States
R01 DK075972 / DK / NIDDK NIH HHS / United States
R01 DK069274 / DK / NIDDK NIH HHS / United States
G0801843 / / Medical Research Council / United Kingdom
F32 DK079541 / DK / NIDDK NIH HHS / United States
RG/10/13/28570 / / British Heart Foundation / United Kingdom
R01 DK064614 / DK / NIDDK NIH HHS / United States
R01DK075972 / DK / NIDDK NIH HHS / United States
R01HD04260 / HD / NICHD NIH HHS / United States
R01DK072301 / DK / NIDDK NIH HHS / United States