Molecular Characteristics
IFT27 (Intraflagellar Transport 27) is located at chromosome 22q12.3 and encodes for a 186 amino acid protein that is a component of the IFT-B complex required for anterograde transport of ciliary protein.
Mutations and pathophysiology
While IFT proteins have been extensively studied in relation to ciliary functions, mutations in IFT genes in humans have typically been associated with skeletal ciliopathies (Jeune asphyxiating thoracic dystrophy, Sensenbrenner syndrome and Mainzer-Saldino syndrome). However, there is evidence of interactions between IFT complexes and BBSomes, particularly in organisms like Caenorhabditis elegans and Chlamydomonas. Notably, IFT27 exhibits distinct characteristics compared to other IFT proteins, such as its resemblance to small GTPases like Rab8 and Rab11, and its formation of a subcomplex with IFT25. Unlike many other IFT proteins, both IFT25 and IFT27 are not conserved in certain organisms, indicating a potentially specialized role in IFT. Additionally, while IFT25 is not essential for cilia formation, it is crucial for proper Hedgehog signalling, similar to several BBS proteins. Given these findings, IFT27 might serve as a link between the BBSome cargo and the IFT machinery.
The first identified mutations in IFT27 were reported in a consanguineous BBS family presenting with RP, obesity, polydactyly, intellectual disability, renal failure, and hypogonadism (Aldahmesh et al., 2014). The patients carried a homozygous missense mutation (c.296G > A, p.Cys99Tyr) predicted to affect the stability of the protein.
Another study identified two compound heterozygous mutations in IFT27 by WES in a child presenting with classical BBS signs (Schaefer et al., 2019). The reported variants are c.104A > G (p.Tyr35Cys) in exon 2 and c.349 + 1G > T affecting splicing of exon 5. The first variant affects the switch I region, possibly affecting GDP/GTP exchange and interacting partners. The second variant leads to exon skipping, previously reported in a fetus with severe phenotype (Quelin et al., 2018).
Another BBS case with RP (cone rod dystrophy), obesity, polydactyly, intellectual and learning delay, and chronic renal failure has been reported by Sanchez-Navarro et al., 2018. However, they could not assess the segregation and the effect on the protein due to the mutation c.[104A>G(;)350-2A>G], p.[Tyr35(;)?].
Lastly, two loss of function mutations in IFT27 have been reported in a fetus presenting with a severe ciliopathy (SRPII or Pallister-Hall syndrome) (Quelin et al., 2018). The mutations, c.[115_122del];[349+1G > T], p.[Thr39Glyfs∗11];[?], were speculated to explain the severe phenotype, including the cardiopathy.
IFT27