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

Publication ,  Journal Article
Davis, EE; Zhang, Q; Liu, Q; Diplas, BH; Davey, LM; Hartley, J; Stoetzel, C; Szymanska, K; Ramaswami, G; Logan, CV; Muzny, DM; Young, AC ...
Published in: Nat Genet
March 2011

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.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2011

Volume

43

Issue

3

Start / End Page

189 / 196

Location

United States

Related Subject Headings

  • Zebrafish
  • Photoreceptor Cells
  • Pedigree
  • Mutation
  • Mice
  • Humans
  • Genetic Variation
  • Developmental Biology
  • Ciliary Motility Disorders
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
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Davis, E. E., Zhang, Q., Liu, Q., Diplas, B. H., Davey, L. M., Hartley, J., … Katsanis, N. (2011). TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet, 43(3), 189–196. https://doi.org/10.1038/ng.756
Davis, Erica E., Qi Zhang, Qin Liu, Bill H. Diplas, Lisa M. Davey, Jane Hartley, Corinne Stoetzel, et al. “TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.Nat Genet 43, no. 3 (March 2011): 189–96. https://doi.org/10.1038/ng.756.
Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189–96.
Davis, Erica E., et al. “TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.Nat Genet, vol. 43, no. 3, Mar. 2011, pp. 189–96. Pubmed, doi:10.1038/ng.756.
Davis 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, NISC Comparative Sequencing Program, 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. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189–196.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2011

Volume

43

Issue

3

Start / End Page

189 / 196

Location

United States

Related Subject Headings

  • Zebrafish
  • Photoreceptor Cells
  • Pedigree
  • Mutation
  • Mice
  • Humans
  • Genetic Variation
  • Developmental Biology
  • Ciliary Motility Disorders
  • Animals