Congenital anomalies of the kidney and urinary tract (CAKUT) - PAX2, HNF1B, BMP4, DSTYK, EYA1, FRAS1, FREM1, FREM2, GREB1L, GRIP1, SALL1, SIX1, SIX2, SIX5, SOX17, TBX18 and WNT4 genes            

Congenital anomalies of the kidney and urinary tract (CAKUT) are a disorder that includes a broad spectrum of urinary tract malformations. These disorders are classified into renal parenchymal abnormalities (renal dysplasia, multicystic renal dysplasia, renal hypoplasia and renal agenesis), renal embryonic migration abnormalities (horseshoe kidney and kidney ectopia), and renal collecting system abnormalities (renal duplication, reflux vesicoureteral, ureteral stenosis, megaureter, bladder exstrophy and posterior urethral valves); Moreover, hydronephrosis may also occur.

The greater or lesser severity of these malformations is mainly conditioned by the number of functional nephrons present at birth, which will dictate the survival time of renal functionality. Congenital anomalies of the kidneys and urinary tract are the most frequent cause of chronic kidney disease in childhood.

It is believed that this disorder is due to a combination of genetic and environmental factors. In most cases the genetic causes of their development are unknown; however, PAX2 (paired box 2) and HNF1B (HNF1 homeobox B) are the genes that have been most frequently associated with CAKUT.

The PAX2 (paired box 2) gene, located on the long arm of chromosome 10 (10q24.31), encodes a protein that participates in the formation of the eyes, ears, central nervous system, kidneys, and urogenital system. It is believed that after birth the PAX2 protein protects against cell death during periods of cellular stress. More than 20 mutations in the PAX2 gene have been described in people with abnormalities of the kidneys and other urinary system structures. Urinary system abnormalities vary in severity, and the most serious can cause kidney failure and life-threatening kidney damage.

The HNF1B (HNF1 homeobox B) gene, located on the long arm of chromosome 17 (17q12), encodes a protein that is part of a large group of transcription factors, known as homeodomain proteins. Homeodomain is a region of the protein that allows it to bind to DNA. It is believed that this protein can play a role in the development of many parts of the body, as it is found in many organs and tissues, including the lungs, liver, intestines, pancreas, kidneys, reproductive system and urinary tract. A large number of the mutations identified in the HNF1B gene in individuals with CAKUT consist of amino acid changes in the HNF1B protein. Other mutations result in abnormal protein synthesis or inhibit the synthesis of any functional protein from a copy of the gene. It is believed that a deficit of functional HNF1B protein is likely to disrupt the regulation of genes that participate in the development of the kidneys and urinary tract.

In addition to the PAX2 and HNF1B genes, mutations in other genes involved in the development of the urinary system have been identified in individuals with CAKUT. These genes include:

  • BMP4 (bone morphogenetic protein 4) (14q22.2).
  • DSTYK (dual serine/threonine and tyrosine protein kinase) (1q32.1).
  • EYA1 (EYA transcriptional coactivator and phosphatase 1) (8q13.3).
  • FRAS1 (Fraser extracellular matrix complex subunit 1) (4q21.21).
  • FREM1 (FRAS1 related extracellular matrix 1) (9p22.3).
  • FREM2 (FRAS1 related extracellular matrix protein 2) (13q13.3).
  • GREB1L (GREB1 like retinoic acid receptor coactivator) (18q11.1-q11.2).
  • GRIP1 (glutamate receptor interacting protein 1) (12q14.3).
  • SALL1 (spalt like transcription factor 1) (16q12.1).
  • SIX1 (SIX homeobox 1) (14q23.1).
  • SIX2 (SIX homeobox 2) (2p21).
  • SIX5 (SIX homeobox 5) (19q13.32).
  • SOX17 (SRY-box 17) (8q11.23).
  • TBX18 (T-box 18) (6q14.3).
  • WNT4 (Wnt family member 4) (1p36.12). 

The inheritance pattern of congenital kidney and urinary tract anomaly (CAKUT) is complex. It is believed that 10 to 20 percent of cases occur in families. When inherited, CAKUT usually follows an autosomal dominant pattern, that is, a copy of the altered gene in each cell is sufficient to give rise to the anomaly. However, some people who have the altered gene never develop CAKUT, a situation known as reduced penetrance. Less frequently, CAKUT follows an autosomal recessive inheritance pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. In many cases, the inheritance pattern is unknown or the condition is not inherited. In some of these cases, the mutation occurs during the formation of the reproductive cells or at the beginning of embryonic development. These cases occur in people with no history of the disorder in their family. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Congenital anomalies of the kidney and urinary tract (CAKUT), by means of the complete PCR amplification of the exons of the PAX2, HNF1B, BMP4, DSTYK, EYA1, FRAS1, FREM1, FREM2, GREB1L, GRIP1, SALL1, SIX1, SIX2, SIX5, SOX17, TBX18 and WNT4 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).