title: Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D003398:Craniosynostoses / Q000235:genetics / Q000473:pathology; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000473:pathology; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
chemical_list: C099883:DYNC2H1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D056445:Cytoplasmic Dyneins; D004398:Dyneins