Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

Halbritter, J., Bizet, A.A., Schmidts, M., Porath, J.D., Braun, D.A., Gee, H.Y., McInerney-Leo, A.M., Krug, P., Filhol, E., Davis, E.E., Airik, R., Czarnecki, P.G., Lehman, A.M., Trnka, P., Nitschké, P., Bole-Feysot, C., Schueler, M., Knebelmann, B., Burtey, S., Szabó, A.J., Tory, K., Leo, P.J., Gardiner, B., McKenzie, F.A., Zankl, A., Brown, M.A., Hartley, J.L., Maher, E.R., Li, C., Leroux, M.R., Scambler, P.J., Zhan, S.H., Jones, S.J., Kayserili, H., Tuysuz, B., Moorani, K.N., Constantinescu, A., Krantz, I.D., Kaplan, B.S., Shah, J.V., Hurd, T.W., Doherty, D., Katsanis, N., Duncan, E.L., Otto, E.A., Beales, P.L., Mitchison, H.M., Saunier, S., and Hildebrandt, F.
American journal of human genetics   93(5): 915-925 (Journal)
Registered Authors
Davis, Erica, Katsanis, Nicholas, Saunier, Sophie
MeSH Terms
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Asians/genetics
  • Bone and Bones/abnormalities
  • Bone and Bones/metabolism
  • Bone and Bones/pathology
  • Cerebellar Ataxia/genetics*
  • Cerebellar Ataxia/pathology
  • Craniosynostoses/genetics
  • Craniosynostoses/pathology
  • Cytoplasmic Dyneins/genetics
  • Cytoplasmic Dyneins/metabolism
  • Dyneins/genetics
  • Dyneins/metabolism
  • Ectodermal Dysplasia/genetics
  • Ectodermal Dysplasia/pathology
  • Ellis-Van Creveld Syndrome/genetics*
  • Ellis-Van Creveld Syndrome/pathology
  • Epistasis, Genetic
  • Female
  • Fibroblasts/pathology
  • Gene Knockdown Techniques
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics*
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Kidney Diseases, Cystic/genetics
  • Kidney Diseases, Cystic/pathology
  • Male
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Retinitis Pigmentosa/genetics*
  • Retinitis Pigmentosa/pathology
  • Whites/genetics
  • Zebrafish/genetics
24140113 Full text @ Am. J. Hum. Genet.

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.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes