Nephronophthisis 2

Alternative Names

  • NPHP2
  • Nephronophthisis, Infantile
  • NPH2

Associated Genes

Nephronophthisis 1
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations of the urinary system

OMIM Number

602088

Mode of Inheritance

Autosomal recessive

Gene Map Locus

9q31

Description

Nephronophthisis is characterized by the development of cysts at the corticomedullary junction, in association with chronic tubulointerstitial nephritis, and is distinguished from other medullary cystic disorders (such as Senior-Loken syndrome and autosomal recessive polycystic kidney disease) in that nephronophthisis has a purely renal pathophysiology. Juvenile nephronophthisis (NPH1) presents late in the first decade of life. This autosomal recessive disorder has been mapped to chromosome 2q13, and recent molecular studies have identified, at this locus, a gene (NPHP1) that is involved in most cases of NPH1. Reports described a group of infants who reached end stage renal disease (ESRD) before 2 years of age, with chronic tubulointerstitial nephritis that had pathological features similar to juvenile nephronophthisis. This disorder has been designated "infantile nephronophthisis" (NPH2).

Molecular Genetics

Nephronophthisis type 2 is caused by mutations in the inversin gene. Human inversin gene is composed of 17 exons; the first exon is noncoding. The gene covers about 100 kb with several introns of 10 kb or more. The INV cDNA contains a 3,195-bp open reading frame coding for 1,065 amino acids. The inversin gene has a dynamic expression pattern throughout the cell cycle with strong expression in the primary cilia of renal epithelium. Inversin protein interacts with the anaphase-promoting complex subunit-2 (APC2) and may play a role in primary cilia function and involvement in the cell cycle. Mutations in the genes encoding the proteins polaris, cystin, and polycystin-2, which are expressed in renal epithelium primary cilia, lead to renal cystic changes. Since aberrant cell proliferation is also involved in cyst development, it is possible that inversin may provide a link between these 2 mechanisms.

Epidemiology in the Arab World

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Other Reports

Palestine

Haider et al. (1998) described a novel type of infantile nephronophthisis in an extended inbred Bedouin kindred with multiple cases of nephronophthisis type 2. The pattern of inheritance within the kindred and the presence of consanguinity indicated an autosomal recessive mode of inheritance. Ten affected subjects (seven males and three females) were the offspring of six Bedouin couples. The manifestations of nephronophthisis type 2 ranged from prenatal fetal oliguria and oligohydramnion resulting in postnatal respiratory failure and death to postnatal onset of disease at 30 months of age. None of the postnatally diagnosed patients had a history of either oligohydramnios or neonatal respiratory symptoms. Histopathologic examination of renal tissues showed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. Renal sonography of all patients revealed enlarged and echogenic kidneys that lacked corticomedullary differentiation. All affected individuals developed anemia, hyperkalemic metabolic acidosis, and increased serum creatinine. The patients were not initially hypertensive; however, hypertension developed concomitantly with the deterioration of renal function. Progression from disease onset to end-stage renal failure or death due to renal complications was rapid (mean time, 7.8 months; range, 3-18 months). None of the affected subjects had polyuria, polydypsia, or associated ocular or hepatic complications. Because of the inbred nature of the family, all the affected individuals were assumed to have descended from a common ancestor. By linkage analysis, Haider et al. (1998) excluded the familial juvenile nephronophthisis locus (NPHP1) on 2q13 and the autosomal recessive polycystic kidney disease locus (PKHD1) on 6p21.1-p12. A homozygosity mapping strategy was employed to search for a locus causing infantile nephronophthisis in this kindred. Pooled DNA samples from parents and unaffected sibs and individual DNA samples from 4 affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, Haider et al. (1998) identified linkage of the clinical phenotype to markers on 9q22-q31. The disorder mapped to a 12.9-cM region flanked by markers D9S280 and GGAT3G09. The INVS gene mapped to the same region.

Saudi Arabia

Al-Hamed et al. (2016) researched antenatal cystic kidney disease in a cohort of 44 Saudi families and aimed to identify the underlying genetic defects.  In one family, the antenatal ultrasound investigation found enlarged, echogenic kidneys, oligohydramnios/anhydramnios, and ventriculomegaly.  The proband had another affected sibling and the case resulted in perinatal death.  A screening of 90 renal genes unveiled a novel homozygous mutation (c.1760delA, p.Q587Rfs*2) in the INVS gene of the patient.  In-silico analysis of the novel frameshift mutation by ‘Mutation Taster’ found it to be disease causing.  The consanguineous parents had another affected child as well as two healthy children.  

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