NEK2

NEK2 (NIMA-related kinase 2) provides the recipe for a serine/threonine kinase, a type of enzyme that helps regulate the process of cell division called mitosis. The protein is found at the centrosome and its level changes across the cell cycle, being undetectable early on and building up as a cell prepares to divide. One of its jobs is to help centrosomes separate and to control the timely assembly and disassembly of cilia. Because the light-sensing cells of the retina rely on a specialized cilium, genes that control ciliary structures, NEK2 among them, can be important for healthy vision.

Retinitis pigmentosa involves the progressive degeneration of the retina, the light-sensing tissue at the back of the eye. NEK2 was identified as a cause of the 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.) form of retinitis pigmentosa, meaning changes were present in both copies of the gene in an affected person. The single reported patient with a NEK2 change had autosomal recessive retinitis pigmentosa, but a report of one person cannot describe the full range of how vision may be affected across everyone who carries changes in this gene.

NEK2 was reported as a new retinitis pigmentosa gene through a study that used whole genome sequencing in 16 unrelated patients with 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.) disease. In one Japanese patient, researchers found a change in both copies of NEK2 (a frameshift, p.L206fs) that was absent from more than 2,500 chromosomes from ethnically matched controls, which supported that the change was disease-causing. When the same researchers inactivated NEK2 in zebrafish, the fish developed retinal 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.) defects, and these defects were corrected by adding back human NEK2 — evidence that the gene is genuinely important for photoreceptor health. Laboratory studies in cultured retinal pigment epithelial cells have shown that NEK2 activity regulates the cilium, including how it is disassembled as cells prepare to divide.

Although NEK2's link to retinitis pigmentosa is recognized, the direct human evidence is limited to essentially a single reported case plus supporting animal work. Because of this, the typical age of onset, the rate of progression, and the range of severity for NEK2-related disease are not well defined. A separate study of the gene CEP250 — whose protein is normally tagged by NEK2 — described an atypical form of Usher syndrome (definition: A genetic condition that causes both retinitis pigmentosa and hearing loss, sometimes with balance problems.) that combines retinitis pigmentosa with hearing loss, but that report concerns CEP250 rather than NEK2 itself, so it should not be read as evidence that NEK2 changes cause hearing loss. Much of the wider scientific work on NEK2 concerns cell division and cancer biology rather than the retina, and those findings do not describe an eye condition.

As of the date of this review, no treatment targeting NEK2 has been approved. Research on NEK2 in the context of vision is at an early, mainly laboratory stage, including cell-culture work on how the protein controls cilia and the zebrafish study showing that human NEK2 could rescue 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.) defects. These findings help explain why the gene matters for the retina but are not themselves treatments.

• Whole genome sequencing identifies NEK2 as a retinitis pigmentosa gene

  Human genetic study (single case) combined with animal (zebrafish) functional work.

  What was found:

  They found a change in both copies of NEK2 (a frameshift, p.L206fs) in one Japanese patient that was absent from more than 2,500 control chromosomes, and inactivating NEK2 in zebrafish caused photoreceptor defects that were corrected by adding human NEK2.

  Why it matters:

  This study introduced NEK2 as a cause of autosomal recessive retinitis pigmentosa and provided functional support that the gene is important for photoreceptor cells.

  Limitation: The human evidence rests on one patient, so the study cannot describe the range of symptoms, onset, or progression of NEK2-related disease.

• NEK2 regulates cilia in retinal pigment epithelial cells

  Laboratory (cultured cell) mechanistic study.

  What was found:

  NEK2 helped remove specific structures from the centrosome before cell division, and altering NEK2 levels changed how cilia were taken apart and reassembled.

  Why it matters:

  It shows NEK2 has a direct role in controlling cilia in retinal-type cells, consistent with cilia being important for the retina.

  Limitation: This is cell-based work and does not directly describe disease or treatment in people.

• NEK2 works with another kinase to control cilia growth and shortening

  Laboratory (cultured cell) mechanistic study.

  What was found:

  The two kinases cooperated to shorten cilia, and blocking NEK2 increased cilium length, while a regulatory protein (PPP1R42) directly inhibited NEK2.

  Why it matters:

  It adds detail on how tightly NEK2 activity must be balanced to keep cilia functioning normally in retinal cells.

  Limitation: Findings are from cell lines and do not establish how these processes play out in human retinal disease.

• A CEP250 change linked to NEK2's tagging site causes atypical Usher syndrome

  Human genetic study of one family.

  What was found:

  A change in CEP250 produced a shortened protein missing the region normally modified by NEK2, and this was associated with early hearing loss and relatively mild retinal degeneration.

  Why it matters:

  It illustrates how NEK2 fits into a network of ciliary proteins whose disruption can affect the retina, though the disease in this family is caused by CEP250, not NEK2.

  Limitation: The study concerns CEP250, so it does not provide direct evidence about disease caused by NEK2 changes.

NEK2-related retinitis pigmentosa has been reported as 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.), which means a person is affected when both inherited copies of the gene carry a change, and the parents are typically unaffected carriers. Siblings of an affected person may also be carriers or, less often, affected, so relatives may find it useful to discuss testing with a genetic counselor. Beyond this inheritance point, the general caregiver guidance shown on every gene page applies here.

• Given that NEK2 is a rare and recently described cause of retinitis pigmentosa, how confident is the laboratory that the change found explains my diagnosis?
• Were changes found in both copies of NEK2, consistent with autosomal recessive inheritance?
• Would testing my parents, siblings, or other relatives help confirm the interpretation of this result?
• What eye monitoring schedule would you recommend for tracking my retinal changes over time?
• Are there any features beyond the retina that you would want to watch for or rule out?
• Would you recommend a referral to a specialist center familiar with inherited retinal disease?

If a NEK2 result is part of your genetic testing, confirming and interpreting it with a genetic counselor or retinal specialist can help clarify what it means for you. Because the human evidence for NEK2 is limited, it is especially worth discussing how confident the laboratory is in this result and whether additional testing of family members would help. You can also use RP Hope's Clinical Trials Finder to explore research relevant to your situation.