Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease

Abstract

Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.

The role of primary cilia in the development and disease of the retina

“…125 IFT140 is essential for normal photoreceptor development in humans. Mutations in human IFT140 are a cause of Mainzer-Saldino syndrome (MZSDS) 131 and ATD, 132 both of which are skeletal ciliopathies that are associated with retinal dystrophy phenotypes. TTC21B, another IFT complex A protein, also localizes to the photoreceptor axoneme, and loss of this protein in mutant mice leads to defective photoreceptor development.…”

The ophthalmic phenotype ofIFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy

“…To date, 15 families with biallelic IFT140 mutations have been reported in the literature, the majority of which had obvious syndromic phenotypes 3 5 6. However, with the exception of two children from two Saudi families who we previously reported,3 the presenting ophthalmic phenotype of children with IFT140 -related retinopathy has not been well characterised.…”

“…Interestingly, those were the only two families in that series without overt childhood renal disease, consistent with the fact that almost all of the children in our series did not have evident renal disease. Schmidts and colleagues6 reported six European patients from six families with compound heterozygous missense and/or nonsense IFT140 mutations; all had evidence for renal and skeletal disease and most appeared to have retinopathy, although the ophthalmic phenotype was not carefully assessed.…”

“…Mutations in genes responsible for IFT-A cause the conorenal syndromes Mainzer-Saldino syndrome (MIM #266920) and, less commonly, Jeune syndrome (MIM %208500) 5 6. Mainzer-Saldino syndrome is characterised by phalangeal cone-shaped epiphyses, chronic renal disease, early-onset retinal dystrophy, and developmental delay.…”

The cilium: a cellular antenna with an influence on obesity risk

“…No (47) COACH Syndrome 216360 Id. No (47) Neuropathy, hereditary sensory, with spastic paraplegia 256840 CCT5 No (48) MOSPGF syndrome 615703 CEP19 Yes (19) Sensenbrenner syndrome (CED3) 614099 IFT43/C14ORF179 No (49) Short-rib thoracic dysplasia 2 611177 IFT80/WDR56 No (50) Meckel Syndrome-like -IFT88 No (51) Sessenbrenner syndrome (CED2) 613610 IFT121/WDR35 No (49) Sensenbrenner syndrome (CED1) 218330 IFT122/WDR10 No (52) Nephronophthisis 12 613820 IFT139/TTC21B No (53,54) Mainzer-Saldino syndrome 266920 IFT140/KIAA0590 No (55) Short-rib thoracic dysplasia 9 266920 Id. No (56) Nephronophthisis 13 614377 IFT144/WDR19 No (57) Retinitis pigmentosa 71 616394 IFT172 Yes (58) Growth hormone deficiency -Id.…”