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Mutations in DSTYK and dominant urinary tract malformations.

ABSTRACT: BACKGROUND:Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS:We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS:Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS:We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

SUBMITTER: Sanna-Cherchi S

PROVIDER: S-EPMC3846391 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Mutations in DSTYK and dominant urinary tract malformations.

Sanna-Cherchi Simone S Sampogna Rosemary V RV Papeta Natalia N Burgess Katelyn E KE Nees Shannon N SN Perry Brittany J BJ Choi Murim M Bodria Monica M Liu Yan Y Weng Patricia L PL Lozanovski Vladimir J VJ Verbitsky Miguel M Lugani Francesca F Sterken Roel R Paragas Neal N Caridi Gianluca G Carrea Alba A Dagnino Monica M Materna-Kiryluk Anna A Santamaria Giuseppe G Murtas Corrado C Ristoska-Bojkovska Nadica N Izzi Claudia C Kacak Nilgun N Bianco Beatrice B Giberti Stefania S Gigante Maddalena M Piaggio Giorgio G Gesualdo Loreto L Vukic Durdica Kosuljandic DK Vukojevic Katarina K Saraga-Babic Mirna M Saraga Marijan M Gucev Zoran Z Allegri Landino L Latos-Bielenska Anna A Casu Domenica D State Matthew M Scolari Francesco F Ravazzolo Roberto R Kiryluk Krzysztof K Al-Awqati Qais Q D'Agati Vivette D VD Drummond Iain A IA Tasic Velibor V Lifton Richard P RP Ghiggeri Gian Marco GM Gharavi Ali G AG

The New England journal of medicine 20130717 7

<h4>Background</h4>Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.<h4>Methods</h4>We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated ...[more]

PMID: 23862974

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Project description:ObjectiveWe analyzed the association between renal and cardiovascular parameters in fetuses with isolated severe urinary tract malformations.Methods39 fetuses at a mean gestational age of 23.6 weeks with nephropathies or urinary tract malformations and markedly impaired or absent renal function were prospectively examined. Fetal echocardiography was performed, and thicknesses of the interventricular septum, and left and right ventricular wall were measured. Blood flow velocity waveforms of the umbilical artery, middle cerebral artery, and ductus venosus were obtained by color Doppler ultrasound. Concentrations of circulating n-terminal pro-B-type natriuretic peptide (nt-proBNP), cystatin C, ß2-microglobulin, and hemoglobin were determined from fetal blood samples.ResultsMalformations included 21 cases of obstructive uropathy, 10 fetuses with bilateral nephropathy, and 8 cases of bilateral renal agenesis. Marked biventricular myocardial hypertrophy was present in all cases. The ratio between measured and gestational age-adjusted normal values was 2.01 (interventricular septum), 1.85, and 1.78 (right and left ventricular wall, respectively). Compared to controls, levels of circulating nt-proBNP were significantly increased (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L); p<0.001). Cystatin C and ß2-microglobulin concentrations were elevated as follows (mean ± SD) 1.85±0.391 mg/L and 8.44±2.423 mg/L, respectively (normal range 1.66±0.202 mg/L and 4.25±0.734 mg/L, respectively). No correlation was detected between cardiovascular parameters and urinary tract morphology and function. Despite increased levels of nt-proBNP cardiovascular function was preserved, with normal fetal Doppler indices in 90.2% of cases.ConclusionUrinary tract malformations resulting in severe renal impairment are associated with biventricular myocardial hypertrophy and elevated concentrations of circulating nt-proBNP during fetal life. Cardiovascular findings do not correlate with kidney function or morphology.

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Mutations in DSTYK and dominant urinary tract malformations.

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Mutations in DSTYK and dominant urinary tract malformations.

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