Alternative titles; symbols
SNOMEDCT: 717749002; DO: 0080207;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q14.3 | Congenital anomalies of kidney and urinary tract 2 | 143400 | Autosomal dominant | 3 | TBX18 | 604613 |
A number sign (#) is used with this entry because of evidence that congenital anomalies of the kidney and urinary tract-2 (CAKUT2) is caused by heterozygous mutation in the TBX18 gene (604613) on chromosome 6q14.
Congenital anomalies of the kidneys and urinary tract (CAKUT) encompasses a spectrum of developmental disorders of the urinary tract that can range from mild vesicoureteral reflux to severe renal agenesis. Other phenotypes include renal duplication, small kidneys, ureteropelvic junction obstruction, hydronephrosis, and renal dysplasia. These abnormalities can result in kidney damage, and possibly renal failure (summary by Vivante et al., 2015).
For a discussion of genetic heterogeneity of CAKUT, see 610805.
Cannon (1954) described a curious family in which 5 males in 3 successive generations had unilateral hydronephrosis. MacKay (1945) observed congenital megaloureters with hydronephrosis in 3 sibs (bilateral in 2). Two other sibs were said to have died of congenital sarcoma of the kidney. The paternal grandfather died of pyonephrosis. The father died of cerebral hemorrhage at 56. Jewell and Buchert (1962) observed 4 cases in 3 generations. Aaron and Robbins (1948) found hydronephrosis without hydroureters and aberrant renal vessels possibly responsible for obstruction at the ureteropelvic junction in sibs.
Simpson and German (1970) described 7 families with multiple cases of urinary tract anomalies, most of them a form of obstructive uropathy, and reviewed the literature on cases in sibs, twins, and other relatives.
McCormack et al. (1981) reported congenital hydronephrosis in father and son, with possible abnormality in earlier generations.
Vivante et al. (2015) reported a 4-generation Hispanic family in which 10 individuals were affected with various congenital anomalies of the kidney and urinary tract, most commonly ureteropelvic junction obstruction (UPJO) resulting in hydronephrosis. Seven affected individuals were described clinically. The age at symptom onset was highly variable, with 1 patient presenting in utero with hydronephrosis and another presenting at age 49 years with hematuria. Additional features included back or flank pain and urinary tract infection. Five of 7 patients underwent surgical intervention for the renal disease. Four additional patients from 2 unrelated Albanian families had various renal abnormalities, including renal asymmetry, small kidneys, and renal duplex. Three of these patients were asymptomatic at presentation between ages 6 and 28 years, although 1 with small kidneys was in renal failure and underwent renal transplantation at age 13 years. The fourth patient presented prenatally with hydronephrosis, megaureter, and ureterocele. An unrelated British patient was found to have bilateral small echogenic kidneys in utero, and subsequently showed vesicoureteral reflux and bilateral renal dysplasia resulting in end-stage kidney disease.
CAKUT2 was mapped to chromosome 6q14 when Vivante et al. (2015) determined that the disorder is caused by mutation in the TBX18 gene.
Early Mapping Studies
In linkage analysis of 5 families with hereditary pelviureteric junction (PUJO), Izquierdo et al. (1992) found linkage to HLA. Maximal lod scores were 3.090 at a recombination fraction of 0.1 with full penetrance, and 2.486 at a recombination fraction of 0.1 with a penetrance of 90%. Use of the HOMOG program suggested genetic heterogeneity with one locus on 6p in 4 of the families and a different locus in 1 family. After exclusion of the unlinked family, 2-point analysis gave a maximal lod score of 3.9 at a recombination fraction of 0.05 with full penetrance, and 4.2 at a recombination fraction of 0.0 with 90% penetrance.
A further suggestion of a 6p locus for hydronephrosis was provided by the observation of Fryns et al. (1993): they performed prenatal diagnosis on a 26-year-old primigravida after the detection of oligohydramnios with bilateral multicystic renal dysplasia on routine echographic examination at 20 weeks' gestation. Chromosomal analysis of the amniotic fluid cell cultures demonstrated translocation t(6;19)(p23.1;q13.4). Examination of the fetus demonstrated bilateral multicystic renal dysplasia with bilateral PUJ obstruction resulting in massive hydronephrosis. Except for external morphologic stigmata and severe lung hypoplasia secondary to the oligohydramnios, no additional malformations were noted. Groenen et al. (1996) stated that an associated von Mayer-Rokitansky-Kuster disorder (277000) was found. Furthermore, the location of the breakpoints in this translocation were revised to 6p21 and 19q13.1.
To elucidate the relationship between the t(6;19) translocation and hereditary hydronephrosis, Groenen et al. (1996) carried out a molecular characterization of a chromosome 19 cosmid clone previously identified as spanning the translocation in the index case. In a fragment straddling the translocation breakpoint, they demonstrated DNA sequences with a high degree of similarity to the USF2 gene (600390) that encodes the transcription factor upstream stimulator factor 2. The chromosome 19 breakpoint in the patient with bilateral multicystic renal dysplasia appeared to have occurred in intron 7 of the USF2 gene. Northern blot analysis of a variety of human tissues revealed that the USF2 gene is ubiquitously expressed. Furthermore, Northern blot and 3-prime RACE analysis of mRNA isolated from lung fibroblasts of the MCRD patient failed to detect a fusion transcript involving USF2 sequences, suggesting gene disruption rather than the generation of a fusion gene as a possible underlying mechanism. Groenen et al. (1998) determined that the chromosome 6 breakpoint in this patient resides in intron 9 of the CDC5L gene (602868).
Raffle (1955) described a family in which 4 members in 2 generations had hydronephrosis. McHale et al. (1996) gave an update on this family, which was shown to contain 9 affected individuals in 3 generations, and excluded linkage to HLA, providing further evidence of genetic heterogeneity in hereditary hydronephrosis. Mackintosh et al. (1989) had also reported a large 'unlinked' family.
Mackintosh et al. (1989) found linkage between familial vesicoureteral reflux (193000) and HLA, suggesting that this disorder may be determined by mutation at the same locus on 6p as multicystic renal dysplasia.
Robson et al. (1994, 1995) proposed that multicystic dysplasia of the kidneys, ureteropelvic junction obstruction, and vesicoureteral reflux may have a common genetic cause.
Santava et al. (1997) studied 4 families with probable autosomal dominant inheritance of congenital hydronephrosis caused by ureteropelvic junction stenosis. In 2 of the families, studies failed to show close linkage to chromosome 6 markers; in the other 2, the findings were consistent with linkage. HLA class I antigen studies were done in all 4 families and class II (HLA-DR; 142860) antigen studies in 3. Male-to-male transmission was observed in 2 of the families.
Male-to-male transmission in several reports of bilateral multicystic renal dysplasia (e.g., Cannon, 1954; McCormack et al., 1981; Santava et al., 1997) indicates autosomal dominant inheritance.
The transmission pattern of UPJO in the Hispanic family reported by Vivante et al. (2015) was consistent with autosomal dominant inheritance.
In affected members of a large multigenerational Hispanic family with UPJO, Vivante et al. (2015) identified a heterozygous truncating mutation in the TBX18 gene (c.1010delG; 604613.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Direct exon sequencing of the TBX18 gene in 1,295 unrelated individuals with CAKUT identified 2 heterozygous missense mutations in the TBX18 gene (604613.0002 and 604613.0003) in 3 families. In vitro functional expression assays in HEK293 cells showed that all the mutant proteins, including the truncating protein, localized properly to the nucleus, were able to homodimerize, and had a prolonged half-life compared to wildtype, all consistent with a dominant-negative effect rather than haploinsufficiency. The 3 proteins also showed significantly less repressive activity compared to wildtype, consistent with a loss of function. Specific studies of the truncating mutation confirmed a dominant-negative dose-dependent effect. Vivante et al. (2015) concluded that the phenotype resulted from impaired ureter smooth muscle cell development during nephrogenesis.
Aaron, G., Robbins, M. A. Hydronephrosis due to aberrant vessels: remarkable familial incidence with report of cases. J. Urol. 60: 702-705, 1948. [PubMed: 18895257] [Full Text: https://doi.org/10.1016/S0022-5347(17)69295-4]
Cannon, J. F. Hereditary unilateral hydronephrosis. Ann. Intern. Med. 41: 1054-1060, 1954. [PubMed: 13208046] [Full Text: https://doi.org/10.7326/0003-4819-41-5-1054]
Fryns, J. P., Kleczkowska, A., Moerman, P., Vandenberghe, K. Hereditary hydronephrosis and the short arm of chromosome 6. (Letter) Hum. Genet. 91: 514-515, 1993. [PubMed: 8357406] [Full Text: https://doi.org/10.1007/BF00217787]
Groenen, P. M. A., Garcia, E., Debeer, P., Devriendt, K., Fryns, J. P., Van de Ven, W. J. M. Structure, sequence, and chromosome 19 localization of human USF2 and its rearrangement in a patient with multicystic renal dysplasia. Genomics 38: 141-148, 1996. [PubMed: 8954795] [Full Text: https://doi.org/10.1006/geno.1996.0609]
Groenen, P. M. A., Garcia, E., Thoelen, R., Aly, M., Schoenmakers, E. F. P. M., Devriendt, K., Fryns, J. P., Van de Ven, W. J. M. Isolation of cosmids corresponding to the chromosome breakpoints of a de novo autosomal translocation, t(6;19)(p21;q13.1), in a patient with multicystic renal dysplasia. Cytogenet. Cell Genet. 75: 210-215, 1996. [PubMed: 9067426] [Full Text: https://doi.org/10.1159/000134485]
Groenen, P. M. A., Vanderlinden, G., Devriendt, K., Fryns, J.-P, Van de Ven, W. J. M. Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia. Genomics 49: 218-229, 1998. [PubMed: 9598309] [Full Text: https://doi.org/10.1006/geno.1998.5254]
Grosse, F. R., Kaveggia, L., Opitz, J. M. Familial hydronephrosis. Z. Kinderheilk. 114: 313-322, 1973. [PubMed: 4726037] [Full Text: https://doi.org/10.1007/BF00569924]
Izquierdo, L., Porteous, M., Paramo, P. G., Connor, J. M. Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p. Hum. Genet. 89: 557-560, 1992. [PubMed: 1634233] [Full Text: https://doi.org/10.1007/BF00219184]
Jewell, J. H., Buchert, W. I. Unilateral hereditary hydronephrosis: a report of four cases in three consecutive generations. J. Urol. 88: 129-136, 1962. [PubMed: 14451767] [Full Text: https://doi.org/10.1016/S0022-5347(17)64752-9]
MacKay, H. Congenital bilateral megalo-ureters with hydronephrosis. A remarkable family history. Proc. Roy. Soc. Med. 38: 567-568, 1945. [PubMed: 19993137]
Mackintosh, M., Almarhoos, G., Heath, D. A. HLA linkage with familial vesicoureteral reflux and familial pelvi-ureteric junction obstruction. Tissue Antigens 34: 185-189, 1989. [PubMed: 2595723] [Full Text: https://doi.org/10.1111/j.1399-0039.1989.tb01735.x]
McCormack, M. K., D'Aguillo, A., Scully, J. Autosomal dominant congenital hydronephrosis (CH): prenatal diagnosis by ultrasound. (Abstract) Am. J. Med. Genet. 33: 85A only, 1981.
McHale, D., Porteous, M. E. M., Wentzel, J., Burn, J. Further evidence of genetic heterogeneity in hereditary hydronephrosis. Clin. Genet. 50: 491-493, 1996. [PubMed: 9147880] [Full Text: https://doi.org/10.1111/j.1399-0004.1996.tb02719.x]
Raffle, R. B. Familial hydronephrosis. Brit. Med. J. 1: 580-582, 1955. [PubMed: 13230561] [Full Text: https://doi.org/10.1136/bmj.1.4913.580]
Robson, W. L. M., Rogers, R. C., Leung, A. K. C. Renal agenesis, multicystic dysplasia, and uretero-pelvic junction obstruction--a common pathogenesis? (Letter) Am. J. Med. Genet. 53: 302 only, 1994. [PubMed: 7856668] [Full Text: https://doi.org/10.1002/ajmg.1320530319]
Robson, W. L. M., Rogers, R. C., Leung, A. K. C. MCDK, UPJO, and VUR: a common genetic cause. (Letter) Am. J. Med. Genet. 59: 398 only, 1995.
Santava, A., Utikalova, A., Bartova, A., Drabek, J., Santavy, J., Scheinar, J. Familial hydronephrosis unlinked to the HLA complex. Am. J. Med. Genet. 70: 118-120, 1997. [PubMed: 9128928] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970516)70:2<118::aid-ajmg3>3.0.co;2-u]
Simpson, J. L., German, J. Familial urinary tract anomalies. (Letter) JAMA 212: 2264 only, 1970. [PubMed: 5467948]
Vivante, A., Kleppa, M.-J., Schulz, J., Kohl, S., Sharma, A., Chen, J., Shril, S., Hwang, D.-Y., Weiss, A.-C., Kaminski, M. M., Shukrun, R., Kemper M. J., and 25 others. Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development. Am. J. Hum. Genet. 97: 291-301, 2015. [PubMed: 26235987] [Full Text: https://doi.org/10.1016/j.ajhg.2015.07.001]