Senior-Løken syndrome is a rare disorder characterized by the combination of two specific features: a kidney condition called nephronophthisis and an eye condition known as Leber congenital amaurosis.

Nephronophthisis causes fluid-filled cysts to develop in the kidneys beginning in childhood. These cysts impair kidney function, initially causing increased urine production (polyuria), excessive thirst (polydipsia), general weakness, and extreme tiredness (fatigue). Nephronophthisis leads to end-stage renal disease (ESRD) later in childhood or in adolescence. ESRD is a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively.

Leber congenital amaurosis primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. This condition causes vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). Some people with Senior-Løken syndrome develop the signs of Leber congenital amaurosis within the first few years of life, while others do not develop vision problems until later in childhood.

Senior-Løken syndrome can be caused by mutations in one of at least five genes. The proteins produced from these genes are known or suspected to play roles in cell structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of cells; they are involved in signaling pathways that transmit information between cells. Cilia are important for the structure and function of many types of cells, including certain cells in the kidneys. They are also necessary for the perception of sensory input (such as vision, hearing, and smell).

Mutations in the genes associated with Senior-Løken syndrome likely lead to problems with the structure and function of cilia. Defects in these cell structures probably disrupt important chemical signaling pathways within cells. Although researchers believe that defective cilia are responsible for the features of this disorder, it remains unclear how they lead specifically to nephronophthisis and Leber congenital amaurosis.

Some people with Senior-Løken syndrome do not have identified mutations in one of the five genes known to be associated with the condition. In these cases, the genetic cause of the disorder is unknown.

Normal Function

The CEP290 gene provides instructions for making a protein that is present in many types of cells, including in the eye's light receptor cells (photoreceptors). Although this protein's function is not well understood, studies suggest that it plays an important role in cell structures called centrosomes and cilia. Centrosomes are involved in cell division and the assembly of microtubules, which are proteins that transport materials in cells and help the cell maintain its shape. Cilia are microscopic, finger-like projections that stick out from the surface of cells. Cilia are involved in cell movement and many different chemical signaling pathways. They are also necessary for the perception of sensory input (such as vision, hearing, and smell). The CEP290 protein is likely necessary for vision by playing a role in transporting proteins within photoreceptors.

Health Conditions Related to Genetic Changes

Leber congenital amaurosis

Many variants (also known as mutations) in the CEP290 gene have been found to cause Leber congenital amaurosis. Leber congenital amaurosis is an eye disorder that primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning near birth or shortly afterward. Variants in the CEP290 gene account for 15 to 22 percent of all cases of Leber congenital amaurosis.

A particular genetic change, written as 2991+1655A>G, is the most common CEP290 gene variant associated with Leber congenital amaurosis. This variant creates a premature stop signal in the instructions for making the CEP290 protein, which reduces the production of functional protein to low levels in cells. Other CEP290 gene changes responsible for this disorder result in the production of abnormally short, completely nonfunctional versions of the CEP290 protein.

It is unclear how variants in the CEP290 gene cause the characteristic features of Leber congenital amaurosis. A shortage of the CEP290 protein clearly affects the development of the retina. Photoreceptors in the retina contain cilia, which are essential for normal vision. Abnormalities involving these cilia may lead to the severe, early visual impairment characteristic of Leber congenital amaurosis.

Bardet-Biedl syndrome

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Joubert syndrome

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Meckel syndrome

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Senior-Løken syndrome

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Other disorders

Several dozen variants in the CEP290 gene have also been identified in other syndromes associated with abnormal cilia. These conditions, which are known as ciliopathies, affect many body systems and include Joubert syndrome, Meckel syndrome, Senior-Løken syndrome, and Bardet-Biedl syndrome (mentioned above). The features of these disorders overlap significantly. They each affect multiple organ systems, most commonly the brain and spinal cord (central nervous system), retina, and kidneys. Meckel syndrome is typically the most severe of the CEP290-associated ciliopathies; affected individuals usually die before or shortly after birth.

The CEP290 gene variants responsible for these disorders lead to the production of an abnormally short version of the CEP290 protein. The abnormal protein likely disrupts cilia function in many different parts of the body. However, it is unclear how variants in this single gene can cause multiple disorders. Researchers speculate that changes in other genes, particularly genes involved in cilia function, may contribute to the varied signs and symptoms of these conditions.

Other Names for This Gene

• 3H11Ag
• BBS14
• cancer/testis antigen 87
• CE290_HUMAN
• centrosomal protein 290kDa
• centrosomal protein of 290 kDa
• CT87
• CTCL tumor antigen se2-2
• FLJ13615
• FLJ21979
• JBTS5
• JBTS6
• KIAA0373
• LCA10
• MKS4
• monoclonal antibody 3H11 antigen
• nephrocytsin-6
• NPHP6
• POC3
• POC3 centriolar protein homolog
• prostate cancer antigen T21
• rd16
• SLSN6
• tumor antigen se2-2

Genomic Location

Normal Function

The NPHP1 gene provides instructions for making the nephrocystin-1 protein. This protein is thought to play a role in cell structures called cilia, which are microscopic, finger-like projections that stick out from the surface of cells. Cilia participate in signaling pathways that transmit information within and between cells and are important for the development and function of many types of cells and tissues. Nephrocystin-1 is found at the base of cilia in cells of the kidneys, respiratory tract, and the light-sensitive tissue at the back of the eye (the retina). Although the specific function of nephrocystin-1 is not well understood, it is thought to interact with a number of other proteins as part of a large protein complex that may be important for normal cilia function.

Health Conditions Related to Genetic Changes

Nephronophthisis

At least 23 mutations in the NPHP1 gene have been found to cause a kidney disorder called nephronophthisis type 1. Type 1 is the most common type of nephronophthisis, accounting for approximately 20 percent of cases of the disorder. Nephronophthisis is characterized by inflammation and scarring of the kidneys and ultimately leads to a life-threatening failure of kidney function (end-stage renal disease or ESRD). In nephronophthisis type 1, ESRD usually occurs around age 13.

The most common genetic change in nephronophthisis type 1 is a large deletion on chromosome 2 that removes the whole NPHP1 gene. Other deletions that remove all or most of the gene or a small portion of the gene can also be involved in this condition. Some mutations change single protein building blocks (amino acids) or lead to an abnormally short nephrocystin-1 protein. It is thought that people with nephronophthisis type 1 have little or no functional nephrocystin-1. The lack of this protein probably impairs the function of cilia in some way, which likely disrupts important chemical signaling pathways during development. Although researchers believe that defective cilia are responsible for the features of nephronophthisis, the mechanism remains unclear.

Joubert syndrome

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Senior-Løken syndrome

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Other disorders

Mutations in the NPHP1 gene can cause syndromes that include nephronophthisis among their features; such conditions are known as nephronophthisis-associated ciliopathies. Senior-Løken syndrome is characterized by the combination of nephronophthisis and breakdown of the retina (retinal degeneration). Joubert syndrome is a multisystem disorder that typically involves neurological problems and can include nephronophthisis, eye abnormalities, liver disease, and other abnormalities. As in nephronophthisis type1 (described above), NPHP1 gene mutations probably impair cilia function. Defective cilia likely cause the features of these nephronophthisis-associated ciliopathies, although it remains unclear how these defects lead to the specific abnormalities of each condition. It is unknown why some individuals with NPHP1 gene mutations develop the additional signs and symptoms of Senior-Løken syndrome or Joubert syndrome.

Other Names for This Gene

• JBTS4
• juvenile nephronophthisis 1 protein
• nephrocystin-1
• nephronophthisis 1 (juvenile)
• NPH1
• SLSN1

Genomic Location

Normal Function

The WDR19 gene (also known as IFT144) provides instructions for making a protein that is involved in the formation and maintenance of cilia, which are microscopic, finger-like projections that stick out from the surface of cells. Cilia participate in signaling pathways that transmit information within and between cells and are important for the development and function of many types of cells and tissues, including cells in the kidneys and liver and the light-sensitive tissue at the back of the eye (the retina). Cilia also play a role in the development of the bones, although the mechanism is not well understood.

The movement of substances within cilia and similar structures called flagella is known as intraflagellar transport. This process is essential for the assembly and maintenance of these cell structures. During intraflagellar transport, cells use molecules called IFT particles to carry materials to and from the tips of cilia. Each IFT particle is made up of two groups of IFT proteins: complex A and complex B. The protein produced from the WDR19 gene forms part of IFT complex A (IFT-A). During intraflagellar transport, this complex carries materials from the tip to the base of cilia.

The IFT-A complex is essential for proper regulation of the Sonic Hedgehog signaling pathway, which is important for the growth and maturation (differentiation) of cells and the normal shaping (patterning) of many parts of the body, especially during embryonic development. The exact role of the complex in this pathway is unclear.

Health Conditions Related to Genetic Changes

Cranioectodermal dysplasia

At least two mutations in the WDR19 gene have been found in individuals with cranioectodermal dysplasia. This condition is characterized by an elongated head (dolichocephaly) with a prominent forehead and other distinctive facial features; short bones; and abnormalities of certain tissues known as ectodermal tissues, which include the teeth, hair, nails, and skin. Cranioectodermal dysplasia can also cause a variety of other problems, including a kidney condition called nephronophthisis and eye abnormalities.

The WDR19 gene mutations involved in cranioectodermal dysplasia reduce the amount of functional WDR19 protein. A shortage or reduction in activity of this component of the IFT-A complex impairs the function of the entire complex, disrupting transport of proteins and materials from the tips of cilia. As a result, assembly and maintenance of cilia is impaired, which leads to a smaller number of cilia and abnormalities in their shape and structure. Although the mechanism is unclear, a loss of normal cilia impedes proper development of bone and other tissues, leading to the features of cranioectodermal dysplasia. Some researchers suggest that disrupted intraflagellar transport prevents signaling through the Sonic Hedgehog pathway, which could impact cell growth and other functions in several tissues throughout the body.

Asphyxiating thoracic dystrophy

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Nephronophthisis

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Retinitis pigmentosa

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Senior-Løken syndrome

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Other Names for This Gene

• ATD5
• CED4
• DYF-2
• FLJ23127
• IFT144
• intraflagellar transport 144 homolog
• KIAA1638
• NPHP13
• ORF26
• Oseg6
• PWDMP
• WDR19_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Senior-Løken syndrome is a rare disorder, with an estimated prevalence of about 1 in 1 million people worldwide. Only a few families with the condition have been described in the medical literature.