Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Nephronophthisis (nephronophthisis) - Genes NPHP1, INVS (NPHP2), NPHP3, NPHP4, IQCB1 (NPHP5), CEP290 (NPHP6), GLIS2 (NPHP7), RPGRIP1L (NPHP8), NEK8 (NPHP9), SDCCAG8 (NPHP10), TMEM67 (NPHP11 ), TTC21B (NPHP12), WDR19 (NPHP13), ZNF423 (NPHP14), CEP164 (NPHP15), ANKS6 (NPHP16), and CEP83 (NPHP18).  

Nephronophthisis (NPH or NPHP), renal impairment is characterized by inflammation and fibrosis that impair renal function. These alterations cause an increase in urine output, excessive thirst, general weakness and fatigue. In addition, affected individuals develop fluid - filled cysts in the kidneys, usually in an area of the spinal cortex. Another feature of the disorder is anemia. Nephronophthisis results in the terminal stage of disease, to severe renal insufficiency. The nephronoptisis can be classified according to the approximate age at which begins renal disease: infantile (onset about 1 year old), Youth (beginning around 13 years) and adolescent (around 19 years old ).

Approximately 85 percent of all cases of nephronoptisis are isolated, which means that occur without other signs and symptoms. Some people with nephronoptisis have additional alterations, which may include liver fibrosis, cardiac abnormalities, or situs inversus. The disease can occur as part of separate syndromes affecting other areas of the body. For example, and Senior-Loken syndrome is characterized by the combination of nephronoptisis retinal degeneration. Joubert syndrome affects many parts of the body, leading to neurological problems and other characteristics, which may include nephronoptisis.

The nephronoptisis has several genetic causes, each of which are used to distinguish different types of disease. The most common cause of nephronophthisis are mutations in the gene NPHP1 (nephrocystin 1), located on the long arm of chromosome 2 (2q13), encoding nefrocistina-1 protein. Mutations in this gene result nephronophthisis type 1, the most common type representing approximately 20 percent of cases of the disease.

The nefrocistina-1 protein is believed to play a role in cilia. Cilia are involved in signaling pathways that transmit information within cells and between cells and some others, as well as being important for the development and function of many cell types and tissues. The protein is found in the base of the cilia of kidney cells, the respiratory tract and retina. Although the specific function of nefrocistina-1 protein is not well understood, it is believed that interacts with other proteins as part of a large protein complex that may be important for the normal function of the cilia. They have identified at least 23 mutations in the gene responsible NPHP1 nephronophthisis type 1. In type 1 nephronophthisis ESRD usually occurs about 13 years. The most frequent type 1 disease genetic change is a deletion on chromosome 2 that removes all the NPHP1 gene. Other deletions suppress all, or most, or a small portion of the gene. Some mutations change amino acids, or give rise to a nefricistina-1 protein abnormally short or nonfunctional. Deficiency or absence of this protein probably somehow affects the function of the cilia, which probably disrupts signaling pathways important chemical during development.

Other common genetic changes involve mutations in INVS (investment) or NPHP2, NPHP3 (nephrocystin 3) and NPHP4 (nephrocystin 4) genes.

The INVS (investment) or NPHP2 gene, located on the long arm of chromosome 9 (9q31), encoding a protein contains several domains and ankyrin two binding domains IQ calmodulin. The encoded protein plays a role in the development and renal tubular function. This protein interacts with the nefrocistina and infers a connection between the primary cilia function and the left-right axis determination. Mutations in this gene have been associated with type 2 nephronophthisis, characterized by early onset and rapid progression. Phenotypic manifestations include swelling of the kidneys, nephritis tubulointerstitial chronic anemia, and metabolic acidosis Hyperkalemic. Some patients also have situs inversus. Pathologically, it differs from nephronophthisis late onset by the absence of medullary cysts, tubular basement membranes thickened, and the presence of cortical microcysts.

The NPHP3 (nephrocystin 3) gene, located on the long arm of chromosome 3 (3q22.1), encodes a protein containing a winding (CC: Coiled coil) a tubulin-tyrosine ligase domain (TTL), and a domain of tetratrico peptide repeat (TPR). The encoded protein interacts with nefocistina, which is required for normal development ciliary, and for renal tubular development. Mutations in this gene are associated with nephronophthisis type 3 characterized by polyuria, polydipsia and anemia. Renal disease is characterized by alterations in tubular basement membranes, tubular atrophy and dilation, tubulointerstitial nephropathy sclerosing, and development of renal cysts predominantly cortical binding.

The NPHP4 (nephrocystin 4) gene, located on the short arm of chromosome 1 (1p36), encodes a protein involved in the development and renal tubular function. This protein interacts with nefrocistina, and is part of a multifunctional complex is located on the actin and microtubule - based structures. Mutations in this gene are associated with type 4 nephronophthisis, resulting in End Stage Renal Disease in the age between 6 and 35 years. Mutations in the gene cause polydipsia, polyuria, anemia and growth retardation. The most prominent histologic features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis , and in advanced stages, medullary cysts.

Besides those mentioned previously genetic changes, other less common changes involved in development of the disease include mutations in the genes:

It is believed that genetic mutations involved in nephronophthisis affect the structure or function of the cilia in some way, probably it disrupts important chemical signaling pathways during development. Although it is believed that faulty cilia result in the characteristics of the nephronoptisis, the mechanism remains unclear. It is unknown why some people with mutations in genes associated with nephronoptisis only have kidney problems, while others develop additional signs and symptoms.

Nephronophthisis is inherited as an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with nephronophthisis by complete PCR amplification of the exons of NPHP1 genes, INVS (NPHP2), NPHP3, NPHP4, IQCB1 (NPHP5), CEP290 (NPHP6), GLIS2 (NPHP7), RPGRIP1L (NPHP8), NEK8 (NPHP9), SDCCAG8 (NPHP10), TMEM67 (NPHP11), TTC21B (NPHP12), WDR19 (NPHP13), ZNF423 (NPHP14), CEP164 (NPHP15), ANKS6 (NPHP16), and CEP83 (NPHP18), respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).