Congenital Anomalies Of Kidney And Urinary Tract 1

A number sign (#) is used with this entry because of evidence that congenital anomalies of the kidney and urinary tract-1 (CAKUT1) is caused by heterozygous mutation in the DSTYK gene (612666) on chromosome 1q32.

Description

Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a broad spectrum of renal and urinary tract malformations. CAKUT structural anomalies range from complete renal agenesis (the most severe), to renal hypodysplasia, multicystic kidney dysplasia, duplex renal collecting system, ureteropelvic junction obstruction (UPJO), megaureter, posterior urethral valves (PUV), and vesicoureteral reflux (VUR). Renal abnormalities are observed in close relatives of up to 10% of CAKUT patients, although these are frequently asymptomatic. The phenotype often does not follow classic mendelian inheritance: family members with the same genetic defect may have variable phenotypes, ranging from severe renal insufficiency to asymptomatic anomalies. CAKUT occurs in about 1 in 500 live births, but are severe enough to cause neonatal death in about 1 in 2,000 births. In addition, CAKUT can occur in syndromic disorders in association with other congenital anomalies, such as papillorenal syndrome (120330) (summary by Renkema et al., 2011).

Genetic Heterogeneity of Congenital Anomalies of Kidney and Urinary Tract

Also see CAKUT2 (143400), caused by mutation in the TBX18 gene (604613) on chromosome 6q14, and CAKUT3 (618270), caused by mutation in the NRIP1 gene (602490) on chromosome 21q.

Clinical Features

Doray et al. (1999) studied a family in which affected individuals in 3 generations had renal dysplasia. The proband was a male fetus, found by ultrasonography at 15 weeks' gestation to have left renal agenesis and right multicystic kidney, absence of bladder, and oligohydramnios. After termination of the pregnancy, the absence of the left kidney was confirmed and numerous cysts were found in the right kidney as well as fibrosis. Whereas the mother was in good health, the father had unilateral renal agenesis which was discovered when he had arterial hypertension at the age of 25 years. The paternal grandfather and his brother had unilateral renal agenesis.

Sanna-Cherchi et al. (2007) studied 7 multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypoplasia. Systemic ultrasonographic screening revealed that many family members harbored malformations such as solitary kidney, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). One large family from Sardinia (K100) had 8 affected individuals. Five had renal hypodysplasia, 1 had a solitary kidney, 1 had asymmetric kidneys, and 1 had infundibulopelvic stenosis. Two of these patients had associated ureteropelvic junction obstruction (UPJO) and 1 had hydrocalix. Three patients had chronic renal failure requiring dialysis.

Sanna-Cherchi et al. (2013) reported 7 unrelated patients with CAKUT; 6 were diagnosed between birth and age 5 years and 1 was diagnosed prenatally. The patients were of Italian or Mediterranean descent. Six had no family history, whereas the seventh had an affected sib. Four had ureteropelvic junction obstruction, 2 had renal hypodysplasia, and 1 had congenital hydronephrosis. Two patients had developed chronic renal failure. A few patients had additional findings, such as hypercalciuria and hearing loss.

Inheritance

The transmission pattern of CAKUT in a family (K100) reported by Sanna-Cherchi et al. (2007) was consistent with autosomal dominant inheritance and incomplete penetrance.

Bound (1943) described unilateral renal agenesis in a boy and his maternal uncle. Gorvoy et al. (1962) described 2 brothers with unilateral renal agenesis.

Buchta et al. (1973) suggested that hereditary renal adysplasia is autosomal dominant, even though the disorder is more common and more severe in males than in females. Buchta et al. (1973) suggested that bilateral renal agenesis is multifactorial with a recurrence risk in sibs of about 1%.

Fitch (1977) concluded that either bilateral or unilateral renal agenesis may be an expression of a single dominant gene.

Based on several affected families, McPherson et al. (1987) concluded that renal adysplasia is most often autosomal dominant with penetrance between 50% and 90%. They estimated an empiric risk of bilateral severe renal adysplasia to be 15 to 20% in the offspring of affected or obligate heterozygotes.

Li Volti et al. (2002) described 3 Sicilian families in which unilateral renal adysplasia was present in 2 consecutive generations.

Cytogenetics

Kidney anomalies consistent with hereditary renal adysplasia were present in the Vancouver family with schizophrenia and segmental aberration of chromosome 5 described by McGillivray et al. (1990).

Mapping

By a genomewide scan in 7 multiplex kindreds segregating nonsyndromic renal hypodysplasia, Sanna-Cherchi et al. (2007) identified significant linkage to a 6.9-Mb segment on 1p33-p32 under an autosomal dominant model with reduced penetrance (peak lod score 3.5 at D1S2652 in the largest kindred). Altogether, 3 of the 7 families showed positive lod scores at this interval, demonstrating heterogeneity of the trait (peak hlod score 3.9, with 45% of families linked). Sanna-Cherchi et al. (2007) stated that the chromosome 1p33-p32 interval contains 52 transcription units, and at least 23 of these are expressed at embryonic day 12.5 in the murine ureteric bud and/or metanephric mesenchyme. Sanna-Cherchi et al. (2007) concluded that these data showed that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identified one locus for this common cause of human kidney failure.

Molecular Genetics

In 7 affected members of a Sardinian family (K100) with congenital anomalies of the kidney and urinary tract, originally reported by Sanna-Cherchi et al. (2007), Sanna-Cherchi et al. (2013) identified a heterozygous splice site mutation in the DSTYK gene (612666.0001). The mutation, which was found by linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation was not present in 5 unaffected family members, but was present in 2 unaffected adults and in 4 family members with an unknown phenotype, suggesting incomplete penetrance. Sequencing of the DSTYK gene in 311 additional patients with CAKUT found 5 additional heterozygous mutations (see, e.g., 612666.0002-612666.0004) in 7 (2.3%) patients. None of these mutations were found in public databases or in 384 European controls. Functional studies of the mutations were not performed. DSTYK mutations predicted to be damaging were found in 14 (0.3%) of 4,300 white controls from the NHLBI Exome Variant Server. Sanna-Cherchi et al. (2013) concluded that carrying a heterozygous DSTYK mutation confers an odds ratio of 7.1 for CAKUT (p = 0.0003). DSTYK was shown to be highly expressed in the maturing epithelia of all major organs and was localized to cell membranes in the ureteric bud and metanephric mesenchyme of the developing kidney. DSTYK knockdown in HEK293T cells inhibited FGF (see 131220)-stimulated phosphorylation of ERK (600997), the principal signal downstream of receptor tyrosine kinases.

Associations Pending Confirmation

For discussion of a possible association between CAKUT and variation in the FOXP1 gene, see 605515.

Pathogenesis

Kiprov et al. (1982) described hyperfiltration injury leading to focal segmental glomerulosclerosis in the normal kidney in unilateral renal agenesis. Hypertension and proteinuria have been observed as long-term consequences of uninephrectomy as in kidney donation (Hakim et al., 1984).

Animal Model

Sanna-Cherchi et al. (2013) demonstrated the morpholino knockdown of the Dstyk ortholog in zebrafish embryos resulted in growth retardation, small fins, abnormal morphogenesis of the tail, and loss of heartbeat. Mutant zebrafish also had cloacal malformations that corresponded to lower genitourinary defects in mammals and defects in jaw development, as well as specific loss of the median fin fold. Pericardial effusion was evident in 5-day-old morphant larvae, which was attributable to both heart and kidney failure. These data suggested an essential role of Dstyk in the development of major organs. The developmental defects resembled phenotypes produced by global loss of FGF signaling.