IFT140

IFT140 makes one subunit of the intraflagellar transport (IFT) complex A, a molecular delivery system that moves cargo along the inside of cilia. Cilia are microscopic, antenna-like structures on the surface of most resting cells that pick up signals from their surroundings — including light — and pass them along. In the retina, the light-sensing photoreceptor (definition: A light-sensing cell in the retina. Rods (used for night and peripheral vision) and cones (used for color and detail) are the two types.) cells rely on this ciliary transport to build and maintain their light-detecting parts, so when IFT140 does not work properly these cells gradually lose function. Because cilia are found throughout the body, changes in IFT140 can also affect other organs, which is why some people have features beyond the eyes.

The most common eye finding reported with IFT140 changes is a retinal dystrophy — a gradual breakdown of the retina's light-sensing cells. Reported symptoms include trouble seeing in dim light (night blindness), a slow narrowing of peripheral vision, and reduced sharpness of vision. In two adult brothers from one family, the condition took the form of a rod-cone dystrophy with lifelong night blindness and progressive loss of peripheral vision, but no problems outside the eyes. In more severe, early-onset cases, children have had poor vision and involuntary eye movements (nystagmus) from birth, along with farsightedness, as well as electroretinogram (definition: A test (often abbreviated ERG) that measures the retina's electrical response to light, used to check how well photoreceptors are working.) testing that showed little or no retinal response. Other people with IFT140 changes have had a milder course, keeping useful vision into their teens or beyond. Because of this wide range, a genetic result in IFT140 does not by itself predict how severe one person's vision changes will be or how quickly they may progress.

The link between IFT140 and retinitis pigmentosa is well established and recognized in clinical genetics references. Researchers have described a spectrum of IFT140-related disease, from a purely ocular (eye-only) form to a syndromic form that involves multiple organs. The syndromic form is often called Mainzer-Saldino syndrome (also known as conorenal syndrome), which classically combines retinal dystrophy with cone-shaped bone ends in the fingers and progressive kidney disease. In a review of 93 reported individuals, features of retinal dystrophy were the most common finding in both the syndromic and eye-only groups. A specific IFT140 change, c.1990G>A (p.Glu664Lys), has appeared repeatedly on the Arabian Peninsula, where it is thought to represent a founder variant or mutational hotspot. Across large gene-testing studies of inherited retinal disease, IFT140 is a comparatively rare cause, identified in a small number of patients. IFT140-related retinal disease has been reported in many populations, including German, Pakistani, Saudi, Iranian, Chinese, and Congolese cohorts.

It is not yet clear why some people with IFT140 changes have eye disease only while others develop a multi-organ syndrome. Laboratory work suggests that some missense changes only partly reduce the transport machinery's function, which the resilient IFT system can sometimes tolerate — this may help explain the range in severity, but the connection between a specific variant and a person's outcome is still being worked out. People with the same variant can present different symptoms, and syndromic issues may reveal themselves over time. For example, an infant who at first appears to only have eye disease may later show kidney or bone involvement.

The supplied evidence does not identify an approved treatment that specifically targets IFT140-related retinal disease. Researchers are, however, exploring gene-based approaches in the laboratory. Because IFT140 is a large gene that does not fit inside a single common gene-therapy carrier, scientists developed a method using several adeno-associated virus (AAV) vectors and a DNA-recombination system to deliver the full gene. In a mouse model of IFT140-associated retinitis pigmentosa, this approach reduced retinal degeneration and preserved visual function. Separately, in laboratory models made from human stem cells — including retinal organoids and retinal pigment cells carrying IFT140 changes — a plant-derived compound called eupatilin improved ciliary transport and the positioning of a key light-sensing protein. These are early animal and cell studies, not treatments available to patients, and much more work would be needed before they could be tested in people.

• Non-syndromic retinitis pigmentosa from IFT140

  Small human case series with supporting laboratory experiments.

  What was found:

  These patients kept useful vision into at least their teens and had normal development without skeletal or kidney disease into adulthood, representing a milder, eye-only form.

  Why it matters:

  It established that IFT140 can cause retinal disease alone, without the systemic features of the classic syndrome.

  Limitation: The number of families was small, and lab findings do not fully explain why disease stays confined to the eyes.

• Gene-delivery strategy tested in mice

  Preclinical laboratory and animal research.

  What was found:

  The method produced full-length protein and, in an IFT140-associated retinitis pigmentosa mouse model, reduced retinal degeneration and preserved visual function.

  Why it matters:

  It shows a possible path toward gene therapy for a gene too large for standard delivery.

  Limitation: Results are from cells and mice only; this is not a treatment available to patients and has not been tested in humans.

• Human stem-cell retinal models and a candidate compound

  Preclinical laboratory research (preprint).

  What was found:

  The models showed abnormal cilia and misplaced light-sensing proteins; treatment with the flavonoid eupatilin improved ciliary transport and protein positioning.

  Why it matters:

  It provides human-based retinal models and identifies a compound worth further study.

  Limitation: This is early cell-based work in a non-peer-reviewed preprint, not evidence of a safe or effective human treatment.

• Eye findings across the full spectrum of IFT140 disease

  Systematic review of previously published human cases.

  What was found:

  Most individuals had eye involvement, and retinal dystrophy was the most common finding in both groups; cataracts and lens clouding were more common in the eye-only form, while crossed eyes (strabismus) were more common in the syndromic form.

  Why it matters:

  It gives a broad picture of how IFT140 affects the eyes and shows that retinal disease is a shared feature regardless of whether other organs are involved.

  Limitation: It relies on earlier reports of varying quality and cannot establish how any one person's disease will progress.

• Severe congenital retinal dystrophy with systemic features

  Human case series.

  What was found:

  All living patients had severe retinal dystrophy with farsightedness, nystagmus, night blindness, and non-recordable retinal responses; all had skeletal abnormalities and many had neurological findings, though chronic kidney failure was not seen.

  Why it matters:

  It documents the more severe, syndromic end of the IFT140 spectrum and highlights a recurring regional variant.

  Limitation: Most patients shared one founder variant, so findings may not represent all IFT140 disease.

Unlike retinal disease caused by many other genes, IFT140 can affect the kidneys and bones, so families may need to be aware of monitoring for kidney disease (including, in severe cases, kidney failure) and skeletal differences such as cone-shaped bone ends in the fingers. Some children with IFT140-related disease have had developmental delay, though this is not universal, and several reported individuals had no problems outside the eyes. Since severe forms frequently begin in infancy or early childhood, early pediatric eye care and, when relevant, kidney and bone screenings may be advised. Since this condition is autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.), both parents of an affected child are typically carriers, which is worth discussing with a genetic counselor when planning for other family members.

• Do my specific IFT140 variants suggest an eye-only form or a form that may involve other organs?
• Would checking my kidney function and bone health now, and over time, be advisable?
• What kind of eye testing will best track how my retina is changing?
• What does an autosomal recessive result mean for my children, siblings, and other relatives?
• Are there systemic symptoms I or my family should watch for and report?
• How can I stay informed about IFT140-related research as it develops?

Because IFT140 can involve the kidneys and skeleton, discussing whether monitoring of kidney function and bone health is appropriate may be useful, even if only eye symptoms are present now. Confirming the exact IFT140 variants and how they are inherited can support accurate genetic counseling for you and your relatives. A precise molecular diagnosis also matters for possible future research participation, since eligibility for gene-based studies typically depends on the confirmed genetic cause. RP Hope's genetic testing resources can help you prepare questions for a genetic counselor. To explore whether any current studies might be relevant, RP Hope's Clinical Trials Finder can screen options with IFT140 in mind.