Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans

Am J Hum Genet. 2013 Nov 7;93(5):915-25. doi: 10.1016/j.ajhg.2013.09.012. Epub 2013 Oct 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Asian Continental Ancestry Group / 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
  • European Continental Ancestry Group / genetics
  • 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
  • Zebrafish / genetics

Substances

  • DYNC2H1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Cytoplasmic Dyneins
  • Dyneins

Supplementary concepts

  • Cranioectodermal Dysplasia
  • Jeune syndrome
  • Mainzer-Saldino Disease