IFT140

Mutations in this gene have been associated to cases of skeletal ciliopathy called Mainzer Saldino Syndrome, characterised by skeletal developmental anomalies, retinal degeneration and a fibrocystic renal disease known as nephronophthisis.[6][7][8] It has also been described in patients with Jeune Syndrome[9] and isolated Lebers congenital amaurosis in the absence of other syndromic features.[10]

Model organisms have been used in the study of IFT140 function. A conditional knockout mouse line called Ift140^{tm1a(KOMP)Wtsi} was generated at the Wellcome Trust Sanger Institute.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping[17]

An ENU derived mouse (cauli) carrying homozygous IFT140 alleles (c.2564T>A, p. I855K) was generated at the Murdoch Children's Research Institute in Melbourne, Australia.[9] The cauli mouse presented with mid-gestational lethality, exencephaly, spina bifida, craniofacial dysmorphism, digital anomalies, cardiac anomalies and somite patterning defects.[9] Ectopic hedgehog signalling was demonstrated by wholemount in situ hybridisation in the limb buds and abnormal morphology of the primary cilium within the limb bud was demonstrated by scanning electron microscopy.[9]

A patient with Mainzer Saldino Syndrome carrying compound heterozygous variants in IFT140 had induced pluripotent stem cells reprogrammed and CRISPR gene corrected before differentiating both stem cell lines into kidney organoids for transcriptional comparison.[8] Aside from validating the club shaped morphology of the primary cilia seen in the cauli mouse limb bud within the regenerated nephron tubules of the IFT140^{c.634G>A/c.2176C>G} organoids compared to the IFT140^WT/c.2176C>G, bulk RNA sequencing comparison demonstrated significant differences in gene pathways related to apicobasal polarity, cell-cell junctions and axonemal dynein assembly.[8]