Nephronophthisis is a disorder that affects the kidneys. It is characterized by inflammation and scarring (fibrosis) that impairs kidney function. These abnormalities lead to increased urine production (polyuria), excessive thirst (polydipsia), general weakness, and extreme tiredness (fatigue). In addition, affected individuals develop fluid-filled cysts in the kidneys, usually in an area known as the corticomedullary region. Another feature of nephronophthisis is a shortage of red blood cells, a condition known as anemia.

Nephronophthisis eventually leads to end-stage renal disease (ESRD), 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. Nephronophthisis can be classified by the approximate age at which ESRD begins: around age 1 (infantile), around age 13 (juvenile), and around age 19 (adolescent).

About 85 percent of all cases of nephronophthisis are isolated, which means they occur without other signs and symptoms. Some people with nephronophthisis have additional features, which can include liver fibrosis, heart abnormalities, or mirror image reversal of the position of one or more organs inside the body (situs inversus).

Nephronophthisis can occur as part of separate syndromes that affect other areas of the body; these are often referred to as nephronophthisis-associated ciliopathies. For example, Senior-Løken syndrome is characterized by the combination of nephronophthisis and a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration); Joubert syndrome affects many parts of the body, causing neurological problems and other features, which can include nephronophthisis.

Nephronophthisis has several genetic causes, which are used to split the condition into distinct types. Nephronophthisis type 1, which is the most common type of the disorder and one cause of juvenile nephronophthisis, results from changes affecting the NPHP1 gene. The proteins produced from NPHP1 and the other genes involved in nephronophthisis 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 and are involved in chemical signaling. Cilia are important for the structure and function of many types of cells and tissues, including cells in the kidneys, liver, brain, and the light-sensitive tissue at the back of the eye (the retina).

The genetic mutations involved in nephronophthisis are thought to impair the structure or function of cilia in some way, which likely disrupts important chemical signaling pathways during development. Although researchers believe that defective cilia lead to the features of nephronophthisis, the mechanism remains unclear. It is unknown why some people with mutations in nephronophthisis-associated genes have only kidney problems, while others develop additional signs and symptoms.

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

MedlinePlus Genetics provides information about Asphyxiating thoracic dystrophy

Nephronophthisis

MedlinePlus Genetics provides information about Nephronophthisis

Retinitis pigmentosa

MedlinePlus Genetics provides information about Retinitis pigmentosa

Senior-Løken syndrome

MedlinePlus Genetics provides information about Senior-Løken syndrome

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.

Nephronophthisis is found in populations worldwide. It occurs in an estimated 1 in 50,000 newborns in Canada, 1 in 100,000 in Finland, and 1 in 922,000 in the United States. Its incidence in other populations is unknown. Nephronophthisis is the most common genetic cause of ESRD in children and young adults.