In the Literature Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene Determinants of Phenotype Commentary on Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic drivers of kidney defects in the DiGeorge syndrome. N Engl J Med. 2017;376(8):742-754. C ongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of pediatric chronic kidney disease in Western coun- tries. 1,2 They represent a spectrum of malformations, including renal dysplasia, duplex kidney, hydro- nephrosis, vesicoureteric reflux, obstructive uropathies such as posterior urethral valve and pelviureteric and ureterovesical junction obstruction, and non- obstructive megaureter, among others. 2-8 The CAKUT spectrum of malformations may be isolated, syndromic with associated extrarenal malformations, or part of other syndromes such as maturity onset diabetes of the young (MODY) and DiGeorge syndrome. 2 The precise cause of CAKUT is unknown; however, these abnor- malities are known to result from missteps during critical stages of kidney development, such as ureteric budding, mesenchymal to epithelial transition, branching morphogenesis, and nephron patterning and elongation. 2-8 Genomic studies have played a signifi- cant role in understanding the pathogenesis of CAKUT and kidney development. Unfortunately, identification of single-gene causes of CAKUT using the classic genetic approach of linkage analysis followed by direct sequencing has been very challenging because of phenotype heterogeneity, 9 and investigators working in this area have been trying to develop efficient ways to unravel the genetic basis of CAKUT. One innovative multistep approach was recently reported by a group of investigators in the United States and Europe. 10 WHAT DOES THIS IMPORTANT STUDY SHOW? This recent study, by multiple groups in the United States and Europe led by a team at Columbia Univer- sity, New York, and published in the New England Journal of Medicine, used a unique approach to map the gene responsible for the renal defects in the 22q11.2 microdeletion that has been recognized for years to be the cause of DiGeorge syndrome. 10 This is the most common microdeletion syndrome in humans, 11 and patients classically present with malformations in multiple organs, including facial anomalies, cardiac defects, neurologic malformations and learning disability, thymic hypoplasia resulting in T-cell defi- ciency, hypoparathyroidism, and CAKUT, among others. 11-13 The prevalence of CAKUT in 22q11.2 microdeletion is w30%. 13 Apart from the association between haploinsufficiency in the transcription factor gene TBX1 and cardiac malformations in 22q11.2 microdeletion, the genetic basis for other phenotypic expression of the microdeletion is unknown. 14 In the study from Lopez-Rivera et al, 10 a large cohort of patients referred with a diagnosis of CAKUT (isolated CAKUT and syndromic CAKUT) were subjected to whole-genome copy number vari- ation analysis followed by: (1) critical examination of the area of overlap in patients with 22q11.2 micro- deletion, (2) molecular genetic characterization of the pathogenicity of candidate genes using high- throughput in vivo phenotyping in zebrafish, (3) sta- tistical analysis to determine the mutation burden in candidate genes, and (4) recapitulation of the CAKUT phenotype using global and tissue-specific knockout of the candidate genes in murine models. Using the multitiered strategy, 9 candidate genes were linked to the renal phenotype in DiGeorge syndrome. 10 Knockdown of 3 of these genes (snap29, aifm3, and crkl) was found to be associated with renal anomalies in zebrafish. Most importantly, it was shown that targeted knockdown in crkl alone was enough to induce the CAKUT phenotype in zebrafish, and pa- tients with isolated CAKUT were found to have pathogenic mutations in the human homolog (CRKL), thus establishing this gene as a new cause of both syndromic and isolated CAKUT. 10 CRKL encodes a 39-kDa Src homology domain– containing adaptor protein with a variety of functions, including cell proliferation, cell migration and adhesion, apoptosis, and the regulation of gene expression. 15,16 George et al 17 showed that targeted deletion of the CRKL gene and its paralog CRK2 in the kidney induces irregular podocyte morphogenesis and progressive proteinuria. The authors determined that the observed defects in podocyte structure and glomerular filtration barrier integrity were due to loss of a critical hetero-oligomeric interaction between CRKL, CRK2, and nephrin at the slit diaphragm. In the present study, Lopez-Rivera et al demonstrate that Originally published online April 26, 2017. Address correspondence to Rasheed A. Gbadegesin, MBBS, MD, Duke Molecular Physiology Institute, Duke University School of Medicine and Duke University Medical Center, Durham, NC 27710. E-mail: [email protected] Ó 2017 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2017.03.017 8 Am J Kidney Dis. 2017;70(1):8-10
Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene Determinants of Phenotype
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Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene Determinants of PhenotypeOriginall Address
MD, Duke M of Medicin NC 27710. 2017 b 0272-638 http://dx.d
8
Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene
Determinants of Phenotype
Commentary on Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic drivers of kidney defects in the DiGeorge syndrome.
N Engl J Med. 2017;376(8):742-754.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of
pediatric chronic kidney disease in Western coun- tries.1,2 They represent a spectrum of malformations, including renal dysplasia, duplex kidney, hydro- nephrosis, vesicoureteric reflux, obstructive uropathies such as posterior urethral valve and pelviureteric and ureterovesical junction obstruction, and non- obstructive megaureter, among others.2-8 The CAKUT spectrum of malformations may be isolated, syndromic with associated extrarenal malformations, or part of other syndromes such as maturity onset diabetes of the young (MODY) and DiGeorge syndrome.2 The precise cause of CAKUT is unknown; however, these abnor- malities are known to result from missteps during critical stages of kidney development, such as ureteric budding, mesenchymal to epithelial transition, branching morphogenesis, and nephron patterning and elongation.2-8 Genomic studies have played a signifi- cant role in understanding the pathogenesis of CAKUT and kidney development. Unfortunately, identification of single-gene causes of CAKUT using the classic genetic approach of linkage analysis followed by direct sequencing has been very challenging because of phenotype heterogeneity,9 and investigators working in this area have been trying to develop efficient ways to unravel the genetic basis of CAKUT. One innovative multistep approach was recently reported by a group of investigators in the United States and Europe.10
WHAT DOES THIS IMPORTANT STUDY SHOW?
This recent study, by multiple groups in the United States and Europe led by a team at Columbia Univer- sity, New York, and published in the New England Journal ofMedicine, used a unique approach tomap the gene responsible for the renal defects in the 22q11.2 microdeletion that has been recognized for years to be the cause of DiGeorge syndrome.10 This is the most common microdeletion syndrome in humans,11 and
y published online April 26, 2017. correspondence to Rasheed A. Gbadegesin, MBBS, olecular Physiology Institute, Duke University School
e and Duke University Medical Center, Durham, E-mail: [email protected] y the National Kidney Foundation, Inc. 6 oi.org/10.1053/j.ajkd.2017.03.017
patients classically present with malformations in multiple organs, including facial anomalies, cardiac defects, neurologic malformations and learning disability, thymic hypoplasia resulting in T-cell defi- ciency, hypoparathyroidism, and CAKUT, among others.11-13 The prevalence of CAKUT in 22q11.2 microdeletion is w30%.13 Apart from the association between haploinsufficiency in the transcription factor gene TBX1 and cardiac malformations in 22q11.2 microdeletion, the genetic basis for other phenotypic expression of the microdeletion is unknown.14
In the study from Lopez-Rivera et al,10 a large cohort of patients referred with a diagnosis of CAKUT (isolated CAKUT and syndromic CAKUT) were subjected to whole-genome copy number vari- ation analysis followed by: (1) critical examination of the area of overlap in patients with 22q11.2 micro- deletion, (2) molecular genetic characterization of the pathogenicity of candidate genes using high- throughput in vivo phenotyping in zebrafish, (3) sta- tistical analysis to determine the mutation burden in candidate genes, and (4) recapitulation of the CAKUT phenotype using global and tissue-specific knockout of the candidate genes in murine models. Using the multitiered strategy, 9 candidate genes were linked to the renal phenotype in DiGeorge syndrome.10
Knockdown of 3 of these genes (snap29, aifm3, and crkl) was found to be associated with renal anomalies in zebrafish. Most importantly, it was shown that targeted knockdown in crkl alone was enough to induce the CAKUT phenotype in zebrafish, and pa- tients with isolated CAKUT were found to have pathogenic mutations in the human homolog (CRKL), thus establishing this gene as a new cause of both syndromic and isolated CAKUT.10
CRKL encodes a 39-kDa Src homology domain– containing adaptor protein with a variety of functions, including cell proliferation, cell migration and adhesion, apoptosis, and the regulation of gene expression.15,16 George et al17 showed that targeted deletion of the CRKL gene and its paralog CRK2 in the kidney induces irregular podocyte morphogenesis and progressive proteinuria. The authors determined that the observed defects in podocyte structure and glomerular filtration barrier integrity were due to loss of a critical hetero-oligomeric interaction between CRKL, CRK2, and nephrin at the slit diaphragm. In the present study, Lopez-Rivera et al demonstrate that
Am J Kidney Dis. 2017;70(1):8-10
In the Literature
isolated knockdown and knockout of the CRKL gene in zebrafish and mice, respectively, recapitulate renal defects observed in patients with DiGeorge syndrome. Furthermore, they showed how neighboring genes (ie, aifm3 and snap29) can interact with one another (genetic epistasis) to produce features consistent with CAKUT phenotype in DiGeorge syndrome (Fig 1). However, it remains unclear how the genes causing CAKUT may interact with genes causing other phe- notypes associated with 22q11.2 microdeletions to produce the complete or incomplete spectrum of phenotypic expression seen in DiGeorge syndrome (Fig 1). Taken together, both these studies highlight the significance of CRKL as a critical mediator of macro- and microarchitectural developmental pro- cesses in the kidney. The study by Lopez-Rivera et al is highly signifi-
cant and innovative because it uses a population- based approach to dissect the genetic basis of a complex phenotype in a highly heterogeneous popu- lation and clearly illustrates the strength of multiple tools to establish the genetic basis of complex syn- dromes. One of the main limitations of the study is the inability to model all 9 candidate genes associated with CAKUT. However, the current findings repre- sent a substantial advance in our understanding of gene-gene interactions in complex hereditary kidney disease. These novel insights may have implications for understanding the genetic basis of other complex malformations and inform the development of tar- geted therapeutics for the treatment of hereditary kidney disease.
CRKL
TBX1
? Figure 1. Proposed mechanism of gene-gene interactions in con
DiGeorge syndrome. Epistatic interactions between CRKL, AIFM3, an Other genes may also contribute to produce the full spectrum of anom TBX1 has been previously established as a cause of the cardiac ma unclear if there are critical gene-gene interactions with TBX1 that DiGeorge syndrome. Finally, the potential pathogenic contribution of typic anomalies associated with DiGeorge syndrome specifically and
Am J Kidney Dis. 2017;70(1):8-10
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES?
Previous approaches to identifying candidate causal CAKUT genes included the use of classic genetic techniques (eg, linkage analysis and direct sequencing) for the interrogation of large pedigrees. More recently, these modalities have been combined with whole- exome sequencing and other next-generation sequencing strategies to accelerate the pace of gene discovery.18 This approach was used in the identifi- cation of CAKUT genes such as ROBO2, DSTYK, and TNXB.9,19,20 However, the method is very challenging because of phenotypic heterogeneity of CAKUT. Consequently, it is not surprising that multiple loci have been reported without a causative gene being identified in some cases.21,22 Others have used a biased candidate gene screening approach in search of mutations in a panel of select genes chosen based on their biological functions and the phenotype induced by disruption of these genes in murine or other animal models. With this approach, Kohl et al23 showed that 12 recessive murine candidate genes were responsible for CAKUT in 2.5% of 574 individuals screened. This approach is laborious, time consuming, and likely more expensive than the approach reported in the study by Lopez-Rivera et al. Furthermore, the candi- date gene approach will not allow for the identification of critical gene-gene interactions that may contribute to genetic renal syndromes. In this regard, one of the major findings of the present study is that complex genetic syndromes with multiorgan involvement may
Complete DiGeorge
Incomplete DiGeorge
c tion
Thymic Hypoplasia
Craniofacial Defects
Neurologic Defects
Learning Disabilities
Other Phenotypes
genital anomalies of the kidney and urinary tract (CAKUT) and d SNAP29 have been shown to recapitulate features of CAKUT. alies characteristic of DiGeorge syndrome. Haploinsufficiency of lformation associated with the 22q11.2 microdeletion. It remains may also contribute to the renal phenotypes characteristic of other genes not characterized in this study to the various pheno- the 22q11.2 microdeletion more broadly are yet to be determined.
9
Hall, Routh, and Gbadegesin
not be inherited in classic Mendelian fashion and that a significant number may be due to epistatic interactions between different genes.
WHAT ARE THE IMPLICATIONS FOR NEPHROLOGISTS?
This study clearly illustrates the merits of using a multiprong approach for understanding the genetic basis of complex malformations and the need for ge- netic testing when such patients are encountered in clinical practice. Currently, the tools clinicians use to treat children with CAKUT are limited: one can reduce urinary tract infection risk with antibiotic prophylaxis or behavioral modification, or one can use surgery to improve the underlying anatomic anomalies.24,25
Thus, from a clinical perspective, it is crucially important to understand the underlying cause of CAKUT in order to target novel therapies for these patients. Evaluating patients with multiple malforma- tions via advanced genetic testing and functional in vivo modeling will lead to a more sophisticated understanding of the pathogenesis of complex devel- opmental disorders. Further, it may uncover funda- mental gene-gene interactions that produce phenotypic variability. To the researcher, the present study shows clearly the power of multidisciplinary collaborative science for the efficient elucidation of the molecular basis of complex medical problems.
Gentzon Hall, MD, PhD Jonathan C. Routh, MD, MPH
Rasheed A. Gbadegesin, MBBS, MD Duke University School of Medicine and Duke
University Medical Center Durham, North Carolina
ACKNOWLEDGEMENTS Support: Dr Gbadegesin is supported by National Institutes of
Health (NIH)/National Institute ofDiabetes andDigestive andKidney Diseases (NIDDK) grants 5R01DK098135 and 5R01DK094987. Dr Hall receives funding through the American Society of Nephrology/ Amos Medical Faculty Development Program and the P&F grant of theDukeO’Brien Center for KidneyResearch. Dr Routh is supported by NIH/NIDDK grant 5K08DK100534. Financial Disclosure: The authors declare that they have no
relevant financial interests. Peer Review: Evaluated by an Associate Editor and Deputy
Editor Berns.
Study (NAPRTCS). Annual Report. Rockville, MD: EMMES Corp; 2014.
2. Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. 2014;29(4):695-704.
3. Vainio S, Lin Y. Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet. 2002;3(7):533-543.
10
4. Ichikawa I, Kuwayama F, Pope JCT, Stephens FD, Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002;61(3):889-898.
5. Dressler GR. Advances in early kidney specification, devel- opment and patterning. Development. 2009;136(23):3863-3874.
6. Schedl A. Renal abnormalities and their developmental origin. Nat Rev Genet. 2007;8(10):791-802.
7. Reidy KJ, Rosenblum ND. Cell and molecular biology of kidney development. Semin Nephrol. 2009;29(4):321-337.
8. Faa G, Gerosa C, Fanni D, et al. Morphogenesis and mo- lecular mechanisms involved in human kidney development. J Cell Physiol. 2012;227(3):1257-1268.
9. Gbadegesin RA, Brophy PD, Adeyemo A, et al. TNXB mutations can cause vesicoureteral reflux. J Am Soc Nephrol. 2013;24(8):1313-1322.
10. Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic drivers of kidney defects in the DiGeorge syndrome. N Engl J Med. 2017;376(8):742-754.
11. Hachamdioglu B, HachamdiogluD,Delil K. 22q11 deletion syndrome: current perspective. Appl Clin Genet. 2015;8:123-132.
12. DiGeorge AM. Discussions on a new concept of the cellular basis of immunology. J Pediatr. 1965;67(5):907-908.
13. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syn- dromes. Lancet. 2007;370(9596):1443-1452.
14. Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362(9393):1366-1373.
15. Feller SM. Crk family adaptors-signalling complex for- mation and biological roles. Oncogene. 2001;20(44):6348-6371.
16. Birge RB, Kalodimos C, Inagaki F, Tanaka S. Crk and CrkL adaptor proteins: networks for physiological and patholog- ical signaling. Cell Commun Signal. 2009;7:13. http://dx.doi.org/ 10.1186/1478-811X-7-13.
17. George B, Fan Q, Dlugos CP, et al. Crk1/2 and CrkL form a hetero-oligomer and functionally complement each other during podocyte morphogenesis. Kidney Int. 2014;85(6):1382-1394.
18. Hall G, Gbadegesin RA. Translating genetic findings in hereditary nephrotic syndrome: the missing loops. Am J Physiol Renal Physiol. 2015;309(1):F24-F28.
19. Lu W, van Eerde AM, Fan X, et al. Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. Am J Hum Genet. 2007;80(4):616-632.
20. Sanna-Cherchi S, Sampogna RV, Papeta N, et al. Muta- tions in DSTYK and dominant urinary tract malformations. N Engl J Med. 2013;369(7):621-629.
21. Darlow JM, Dobson MG, Darlay R, et al. A new genome scan for primary nonsyndromic vesicoureteric reflux emphasizes high genetic heterogeneity and shows linkage and association with various genes already implicated in urinary tract development.Mol Genet Genomic Med. 2014;2(1):7-29.
22. Weng PL, Sanna-Cherchi S, Hensle T, et al. A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13. J Am Soc Nephrol. 2009;20(7):1633-1640.
23. Kohl S, Hwang DY, Dworschak GC, et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2014;25(9):1917-1922.
24. Wang HH, Gbadegesin RA, Foreman JW, et al. Efficacy of antibiotic prophylaxis in children with vesicoureteral reflux: sys- tematic review and meta-analysis. J Urol. 2015;193(3):963-969.
25. Routh JC, Bogaert GA, Kaefer M, et al. Vesicoureteral reflux: current trends in diagnosis, screening, and treatment. Eur Urol. 2012;61(4):773-782.
Am J Kidney Dis. 2017;70(1):8-10
What Does This Important Study Show?
How Does This Study Compare With Prior Studies?
What are the Implications for Nephrologists?
Acknowledgements
References
MD, Duke M of Medicin NC 27710. 2017 b 0272-638 http://dx.d
8
Urinary Anomalies in 22q11.2 Deletion (DiGeorge syndrome): From Copy Number Variations to Single-Gene
Determinants of Phenotype
Commentary on Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic drivers of kidney defects in the DiGeorge syndrome.
N Engl J Med. 2017;376(8):742-754.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of
pediatric chronic kidney disease in Western coun- tries.1,2 They represent a spectrum of malformations, including renal dysplasia, duplex kidney, hydro- nephrosis, vesicoureteric reflux, obstructive uropathies such as posterior urethral valve and pelviureteric and ureterovesical junction obstruction, and non- obstructive megaureter, among others.2-8 The CAKUT spectrum of malformations may be isolated, syndromic with associated extrarenal malformations, or part of other syndromes such as maturity onset diabetes of the young (MODY) and DiGeorge syndrome.2 The precise cause of CAKUT is unknown; however, these abnor- malities are known to result from missteps during critical stages of kidney development, such as ureteric budding, mesenchymal to epithelial transition, branching morphogenesis, and nephron patterning and elongation.2-8 Genomic studies have played a signifi- cant role in understanding the pathogenesis of CAKUT and kidney development. Unfortunately, identification of single-gene causes of CAKUT using the classic genetic approach of linkage analysis followed by direct sequencing has been very challenging because of phenotype heterogeneity,9 and investigators working in this area have been trying to develop efficient ways to unravel the genetic basis of CAKUT. One innovative multistep approach was recently reported by a group of investigators in the United States and Europe.10
WHAT DOES THIS IMPORTANT STUDY SHOW?
This recent study, by multiple groups in the United States and Europe led by a team at Columbia Univer- sity, New York, and published in the New England Journal ofMedicine, used a unique approach tomap the gene responsible for the renal defects in the 22q11.2 microdeletion that has been recognized for years to be the cause of DiGeorge syndrome.10 This is the most common microdeletion syndrome in humans,11 and
y published online April 26, 2017. correspondence to Rasheed A. Gbadegesin, MBBS, olecular Physiology Institute, Duke University School
e and Duke University Medical Center, Durham, E-mail: [email protected] y the National Kidney Foundation, Inc. 6 oi.org/10.1053/j.ajkd.2017.03.017
patients classically present with malformations in multiple organs, including facial anomalies, cardiac defects, neurologic malformations and learning disability, thymic hypoplasia resulting in T-cell defi- ciency, hypoparathyroidism, and CAKUT, among others.11-13 The prevalence of CAKUT in 22q11.2 microdeletion is w30%.13 Apart from the association between haploinsufficiency in the transcription factor gene TBX1 and cardiac malformations in 22q11.2 microdeletion, the genetic basis for other phenotypic expression of the microdeletion is unknown.14
In the study from Lopez-Rivera et al,10 a large cohort of patients referred with a diagnosis of CAKUT (isolated CAKUT and syndromic CAKUT) were subjected to whole-genome copy number vari- ation analysis followed by: (1) critical examination of the area of overlap in patients with 22q11.2 micro- deletion, (2) molecular genetic characterization of the pathogenicity of candidate genes using high- throughput in vivo phenotyping in zebrafish, (3) sta- tistical analysis to determine the mutation burden in candidate genes, and (4) recapitulation of the CAKUT phenotype using global and tissue-specific knockout of the candidate genes in murine models. Using the multitiered strategy, 9 candidate genes were linked to the renal phenotype in DiGeorge syndrome.10
Knockdown of 3 of these genes (snap29, aifm3, and crkl) was found to be associated with renal anomalies in zebrafish. Most importantly, it was shown that targeted knockdown in crkl alone was enough to induce the CAKUT phenotype in zebrafish, and pa- tients with isolated CAKUT were found to have pathogenic mutations in the human homolog (CRKL), thus establishing this gene as a new cause of both syndromic and isolated CAKUT.10
CRKL encodes a 39-kDa Src homology domain– containing adaptor protein with a variety of functions, including cell proliferation, cell migration and adhesion, apoptosis, and the regulation of gene expression.15,16 George et al17 showed that targeted deletion of the CRKL gene and its paralog CRK2 in the kidney induces irregular podocyte morphogenesis and progressive proteinuria. The authors determined that the observed defects in podocyte structure and glomerular filtration barrier integrity were due to loss of a critical hetero-oligomeric interaction between CRKL, CRK2, and nephrin at the slit diaphragm. In the present study, Lopez-Rivera et al demonstrate that
Am J Kidney Dis. 2017;70(1):8-10
In the Literature
isolated knockdown and knockout of the CRKL gene in zebrafish and mice, respectively, recapitulate renal defects observed in patients with DiGeorge syndrome. Furthermore, they showed how neighboring genes (ie, aifm3 and snap29) can interact with one another (genetic epistasis) to produce features consistent with CAKUT phenotype in DiGeorge syndrome (Fig 1). However, it remains unclear how the genes causing CAKUT may interact with genes causing other phe- notypes associated with 22q11.2 microdeletions to produce the complete or incomplete spectrum of phenotypic expression seen in DiGeorge syndrome (Fig 1). Taken together, both these studies highlight the significance of CRKL as a critical mediator of macro- and microarchitectural developmental pro- cesses in the kidney. The study by Lopez-Rivera et al is highly signifi-
cant and innovative because it uses a population- based approach to dissect the genetic basis of a complex phenotype in a highly heterogeneous popu- lation and clearly illustrates the strength of multiple tools to establish the genetic basis of complex syn- dromes. One of the main limitations of the study is the inability to model all 9 candidate genes associated with CAKUT. However, the current findings repre- sent a substantial advance in our understanding of gene-gene interactions in complex hereditary kidney disease. These novel insights may have implications for understanding the genetic basis of other complex malformations and inform the development of tar- geted therapeutics for the treatment of hereditary kidney disease.
CRKL
TBX1
? Figure 1. Proposed mechanism of gene-gene interactions in con
DiGeorge syndrome. Epistatic interactions between CRKL, AIFM3, an Other genes may also contribute to produce the full spectrum of anom TBX1 has been previously established as a cause of the cardiac ma unclear if there are critical gene-gene interactions with TBX1 that DiGeorge syndrome. Finally, the potential pathogenic contribution of typic anomalies associated with DiGeorge syndrome specifically and
Am J Kidney Dis. 2017;70(1):8-10
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES?
Previous approaches to identifying candidate causal CAKUT genes included the use of classic genetic techniques (eg, linkage analysis and direct sequencing) for the interrogation of large pedigrees. More recently, these modalities have been combined with whole- exome sequencing and other next-generation sequencing strategies to accelerate the pace of gene discovery.18 This approach was used in the identifi- cation of CAKUT genes such as ROBO2, DSTYK, and TNXB.9,19,20 However, the method is very challenging because of phenotypic heterogeneity of CAKUT. Consequently, it is not surprising that multiple loci have been reported without a causative gene being identified in some cases.21,22 Others have used a biased candidate gene screening approach in search of mutations in a panel of select genes chosen based on their biological functions and the phenotype induced by disruption of these genes in murine or other animal models. With this approach, Kohl et al23 showed that 12 recessive murine candidate genes were responsible for CAKUT in 2.5% of 574 individuals screened. This approach is laborious, time consuming, and likely more expensive than the approach reported in the study by Lopez-Rivera et al. Furthermore, the candi- date gene approach will not allow for the identification of critical gene-gene interactions that may contribute to genetic renal syndromes. In this regard, one of the major findings of the present study is that complex genetic syndromes with multiorgan involvement may
Complete DiGeorge
Incomplete DiGeorge
c tion
Thymic Hypoplasia
Craniofacial Defects
Neurologic Defects
Learning Disabilities
Other Phenotypes
genital anomalies of the kidney and urinary tract (CAKUT) and d SNAP29 have been shown to recapitulate features of CAKUT. alies characteristic of DiGeorge syndrome. Haploinsufficiency of lformation associated with the 22q11.2 microdeletion. It remains may also contribute to the renal phenotypes characteristic of other genes not characterized in this study to the various pheno- the 22q11.2 microdeletion more broadly are yet to be determined.
9
Hall, Routh, and Gbadegesin
not be inherited in classic Mendelian fashion and that a significant number may be due to epistatic interactions between different genes.
WHAT ARE THE IMPLICATIONS FOR NEPHROLOGISTS?
This study clearly illustrates the merits of using a multiprong approach for understanding the genetic basis of complex malformations and the need for ge- netic testing when such patients are encountered in clinical practice. Currently, the tools clinicians use to treat children with CAKUT are limited: one can reduce urinary tract infection risk with antibiotic prophylaxis or behavioral modification, or one can use surgery to improve the underlying anatomic anomalies.24,25
Thus, from a clinical perspective, it is crucially important to understand the underlying cause of CAKUT in order to target novel therapies for these patients. Evaluating patients with multiple malforma- tions via advanced genetic testing and functional in vivo modeling will lead to a more sophisticated understanding of the pathogenesis of complex devel- opmental disorders. Further, it may uncover funda- mental gene-gene interactions that produce phenotypic variability. To the researcher, the present study shows clearly the power of multidisciplinary collaborative science for the efficient elucidation of the molecular basis of complex medical problems.
Gentzon Hall, MD, PhD Jonathan C. Routh, MD, MPH
Rasheed A. Gbadegesin, MBBS, MD Duke University School of Medicine and Duke
University Medical Center Durham, North Carolina
ACKNOWLEDGEMENTS Support: Dr Gbadegesin is supported by National Institutes of
Health (NIH)/National Institute ofDiabetes andDigestive andKidney Diseases (NIDDK) grants 5R01DK098135 and 5R01DK094987. Dr Hall receives funding through the American Society of Nephrology/ Amos Medical Faculty Development Program and the P&F grant of theDukeO’Brien Center for KidneyResearch. Dr Routh is supported by NIH/NIDDK grant 5K08DK100534. Financial Disclosure: The authors declare that they have no
relevant financial interests. Peer Review: Evaluated by an Associate Editor and Deputy
Editor Berns.
Study (NAPRTCS). Annual Report. Rockville, MD: EMMES Corp; 2014.
2. Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. 2014;29(4):695-704.
3. Vainio S, Lin Y. Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet. 2002;3(7):533-543.
10
4. Ichikawa I, Kuwayama F, Pope JCT, Stephens FD, Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002;61(3):889-898.
5. Dressler GR. Advances in early kidney specification, devel- opment and patterning. Development. 2009;136(23):3863-3874.
6. Schedl A. Renal abnormalities and their developmental origin. Nat Rev Genet. 2007;8(10):791-802.
7. Reidy KJ, Rosenblum ND. Cell and molecular biology of kidney development. Semin Nephrol. 2009;29(4):321-337.
8. Faa G, Gerosa C, Fanni D, et al. Morphogenesis and mo- lecular mechanisms involved in human kidney development. J Cell Physiol. 2012;227(3):1257-1268.
9. Gbadegesin RA, Brophy PD, Adeyemo A, et al. TNXB mutations can cause vesicoureteral reflux. J Am Soc Nephrol. 2013;24(8):1313-1322.
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Am J Kidney Dis. 2017;70(1):8-10
What Does This Important Study Show?
How Does This Study Compare With Prior Studies?
What are the Implications for Nephrologists?
Acknowledgements
References
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