IFT140, Intraflagellar transport 140 homolog, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''IFT140''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The gene product forms a core component of IFT-A complex which is indipensible for retrograde

intraflagellar transport Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that ass ...

within the

primary cilium The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...

Clinical significance

Mutations in this gene have been associated to cases of skeletal

ciliopathy A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function whi ...

called Mainzer Saldino Syndrome, characterised by skeletal developmental anomalies, retinal degeneration and a fibrocystic renal disease known as nephronophthisis. It has also been described in patients with Jeune Syndrome and isolated Lebers congenital amaurosis in the absence of other syndromic features.

Model organisms

Model organisms have been used in the study of IFT140 function. A conditional

knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importa ...

line called ''Ift140^{tm1a(KOMP)Wtsi}'' was generated at the

Wellcome Trust Sanger Institute The Wellcome Sanger Institute, previously known as The Sanger Centre and Wellcome Trust Sanger Institute, is a non-profit British genomics and genetics research institute, primarily funded by the Wellcome Trust. It is located on the Wellcome G ...

. Male and female animals underwent a standardized

phenotypic screen In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping An ENU derived mouse (''cauli'') carrying homozygous ''IFT140'' alleles (c.2564T>A, p. I855K) was generated at the

Murdoch Children's Research Institute The Murdoch Children's Research Institute (MCRI) is an Australian paediatric medical research institute located in Melbourne, Victoria, affiliated with the Royal Children's Hospital and the University of Melbourne. The institute has six research ...

in Melbourne, Australia. The ''cauli'' mouse presented with mid-gestational lethality, exencephaly, spina bifida, craniofacial dysmorphism, digital anomalies, cardiac anomalies and somite patterning defects. 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. A patient with Mainzer Saldino Syndrome carrying

compound heterozygous In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disorders, genetic disease in a heterozygous state; that is, an organism is a compound h ...

variants in ''IFT140'' had

induced pluripotent stem cell Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in ...

s reprogrammed and CRISPR gene corrected before differentiating both stem cell lines into kidney

organoid An organoid is a miniaturized and simplified version of an organ produced in vitro in three dimensions that shows realistic micro-anatomy. They are derived from one or a few cells from a tissue, embryonic stem cells or induced pluripotent stem ...

s for transcriptional comparison. 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.

References

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