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1.
J Med Genet ; 60(6): 587-596, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36379543

RESUMO

BACKGROUND: SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system. METHODS: Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development. RESULTS: In this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino. CONCLUSION: The identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.


Assuntos
Sistema Cardiovascular , Sistema Urinário , Gravidez , Feminino , Humanos , Animais , Camundongos , Peixe-Zebra/genética , Variações do Número de Cópias de DNA , Morfolinos , Sistema Urinário/anormalidades , Sistema Nervoso Central
2.
Am J Hum Genet ; 104(5): 994-1006, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31051115

RESUMO

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.


Assuntos
Aberrações Cromossômicas , Proteínas de Ligação a DNA/genética , Doenças Fetais/genética , Mutação , Obstrução do Colo da Bexiga Urinária/congênito , Obstrução do Colo da Bexiga Urinária/genética , Adulto , Animais , Criança , Feminino , Doenças Fetais/patologia , Genes Dominantes , Idade Gestacional , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Gravidez , Obstrução do Colo da Bexiga Urinária/patologia , Peixe-Zebra
3.
Nephrol Dial Transplant ; 37(12): 2351-2362, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-35772019

RESUMO

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.


Assuntos
Nefropatias , Insuficiência Renal , Anormalidades Urogenitais , Criança , Humanos , Rim/patologia , Nefropatias/patologia , Insuficiência Renal/patologia
4.
Am J Med Genet A ; 185(12): 3784-3792, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34338422

RESUMO

The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.


Assuntos
Malformações Anorretais/genética , Atresia Esofágica/genética , Predisposição Genética para Doença , Cardiopatias/genética , Fístula Traqueoesofágica/genética , Malformações Anorretais/complicações , Malformações Anorretais/patologia , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Atresia Esofágica/complicações , Atresia Esofágica/patologia , Feminino , Genes Ligados ao Cromossomo X/genética , Estudos de Associação Genética , Proteínas de Choque Térmico HSP90/genética , Cardiopatias/complicações , Cardiopatias/patologia , Hemizigoto , Proteínas de Homeodomínio/genética , Humanos , Rim/anormalidades , Masculino , Receptores de Interleucina/genética , Fístula Traqueoesofágica/complicações , Fístula Traqueoesofágica/patologia , Fatores de Transcrição/genética , Sequenciamento do Exoma
6.
Birth Defects Res A Clin Mol Teratol ; 106(8): 724-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27223093

RESUMO

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is characterized by a spectrum of genitourinary malformations. Both classical bladder exstrophy and the most severe phenotype, exstrophy of the cloaca, display omphaloceles, a cardinal anomaly of some disorders caused by altered imprinting. Therefore, we hypothesized that BEEC in some patients could occur on the basis of an undiagnosed imprinting disorder. Such altered imprinting is associated with changes in the parent-of-origin-specific DNA methylation. METHODS: We analyzed the DNA methylation of 54 imprinted loci in 23 selected patients with different BEEC subtypes (epispadias n = 1, classical bladder exstrophy n = 10, exstrophy of the cloaca n = 12) using the Infinium HumanMethylation450 BeadChip. A total of 471,722 not imprinted autosomal CpG loci and 891 imprinted CpG loci were investigated. Findings were corroborated by methylation-specific-multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite analysis. RESULTS: No significant differences in the DNA methylation of the not imprinted and imprinted CpG were observed depending on subtype of BEEC. Nevertheless, in 1 of the 23 patients who displayed a classical bladder exstrophy, we detected hypomethylation of the imprinted PLAGL1 locus in chromosome 6q24. We verified this hypomethylation by MS-MLPA and showed further the methylation loss to be caused most likely by a mosaic epimutation. CONCLUSION: Considering that it is highly unlikely to detect a PLAGL1 epimutation among 23 individuals given the low incidence of this alteration in the population, our observations further support a link between BEEC and imprinting disorders. Birth Defects Research (Part A) 106:724-728, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Extrofia Vesical/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 6/química , Metilação de DNA , Epispadia/genética , Impressão Genômica , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Extrofia Vesical/diagnóstico , Extrofia Vesical/patologia , Criança , Pré-Escolar , Estudos de Coortes , Ilhas de CpG , Epispadia/diagnóstico , Epispadia/patologia , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Masculino , Repetições de Microssatélites , Reação em Cadeia da Polimerase Multiplex
7.
Pediatr Nephrol ; 31(11): 2025-33, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26857713

RESUMO

The acronym VATER/VACTERL association (OMIM #192350) refers to the rare non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). According to epidemiological studies, the majority of patients with VATER/VACTERL association present with a "Renal" phenotype comprising a large spectrum of congenital renal anomalies. This finding is supported by evidence linking all of the human disease genes for the VATER/VACTERL association identified to date, namely, FGF8, FOXF1, HOXD13, LPP, TRAP1, and ZIC3, with renal malformations. Here we review these genotype-phenotype correlations and suggest that the elucidation of the genetic causes of the VATER/VACTERL association will ultimately provide insights into the genetic causes of the complete spectrum of congenital renal anomalies per se.


Assuntos
Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Anus Imperfurado/genética , Esôfago/anormalidades , Cardiopatias Congênitas/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Rádio (Anatomia)/anormalidades , Doenças Raras/genética , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Anormalidades Múltiplas/epidemiologia , Anus Imperfurado/epidemiologia , Proteínas do Citoesqueleto/genética , Fator 8 de Crescimento de Fibroblasto/genética , Fatores de Transcrição Forkhead/genética , Genótipo , Proteínas de Choque Térmico HSP90/genética , Cardiopatias Congênitas/epidemiologia , Proteínas de Homeodomínio/genética , Humanos , Proteínas com Domínio LIM/genética , Deformidades Congênitas dos Membros/epidemiologia , Mutação , Fenótipo , Prevalência , Doenças Raras/epidemiologia , Fatores de Transcrição/genética
8.
Twin Res Hum Genet ; 19(1): 60-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26681452

RESUMO

By definition, monozygotic (MZ) twins carry an identical set of genetic information. The observation of early post-twinning mutational events was shown to cause phenotypic discordance among MZ twin pairs. These mutational events comprise genomic alterations at different scales, ranging from single nucleotide changes to larger copy-number variations (CNVs) of varying sizes, as well as epigenetic changes. Here, we performed whole-exome sequencing (WES) in nine discordant MZ twins to identify somatic mutational events in the affected twin that might exert a dominant negative effect. Five of these MZ twin pairs were discordant for congenital heart defects (CHD), two for endocrine disorders, one for omphalocele, and one for congenital diaphragmatic hernia (CDH). Analysis of WES data from all nine MZ twin pairs using the de novo probability tool DeNovoGear detected only one apparent de novo variation in TMPRSS13 in one of the CHD-affected twins. Analysis of WES data from all nine MZ twin pairs by using standard filter criteria without the de novo probability tool DeNovoGear revealed a total of 6,657 variations in which both the twin pairs differed. After filtering for variations only present in the affected twins and absent in in-house controls, 722 variations remained. Visual inspection for read quality decreased this number to 12, present only in the affected twin. However, Sanger sequencing of the overall 13 variations failed to confirm the variation in the affected twin. These results suggest that somatic mutational events in coding regions do not seem to play a major role in the phenotypic expression of MZ discordant twin pairs.


Assuntos
Doenças em Gêmeos/genética , Exoma , Análise de Sequência de DNA , Gêmeos Monozigóticos/genética , Variações do Número de Cópias de DNA , Doenças do Sistema Endócrino/genética , Feminino , Cardiopatias Congênitas/genética , Hérnia Umbilical/genética , Hérnias Diafragmáticas Congênitas/genética , Humanos , Masculino , Mutação , Fenótipo
9.
Hum Mutat ; 36(12): 1150-4, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26294094

RESUMO

The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease-associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease-causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.


Assuntos
Canal Anal/anormalidades , Anus Imperfurado/genética , Esôfago/anormalidades , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Proteínas de Homeodomínio/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Rádio (Anatomia)/anormalidades , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Fatores de Transcrição/genética , Alelos , Animais , Anus Imperfurado/diagnóstico , Cílios/genética , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Fatores de Transcrição Forkhead/metabolismo , Genótipo , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Camundongos , Mutação , Fenótipo , Fatores de Transcrição/metabolismo
10.
Hum Genet ; 134(8): 905-16, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26026792

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.


Assuntos
Proteínas Ativadoras de GTPase , Peptídeos e Proteínas de Sinalização Intercelular , Mutação , Proteínas do Tecido Nervoso , Receptores Imunológicos , Transdução de Sinais/genética , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Exoma , Proteínas Ativadoras de GTPase/biossíntese , Proteínas Ativadoras de GTPase/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/metabolismo , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fatores de Risco , Anormalidades Urogenitais/embriologia , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/embriologia , Refluxo Vesicoureteral/genética
11.
Birth Defects Res A Clin Mol Teratol ; 103(4): 235-42, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25250690

RESUMO

BACKGROUND: Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes. METHODS: In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM. RESULTS: In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM. CONCLUSION: The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.


Assuntos
Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Anus Imperfurado/genética , Sistema Nervoso Central/anormalidades , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Reto/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Canal Anal/patologia , Malformações Anorretais , Anus Imperfurado/patologia , Criança , Mapeamento Cromossômico/métodos , Feminino , Haplótipos/genética , Humanos , Cariotipagem , Masculino , Reto/patologia , Adulto Jovem
12.
J Am Soc Nephrol ; 25(9): 1917-22, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24700879

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.


Assuntos
Proteínas de Transporte/genética , Proteínas da Matriz Extracelular/genética , Síndrome de Fraser/genética , Cadeias alfa de Integrinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/anormalidades , Mutação , Proteínas do Tecido Nervoso/genética , Receptores de Interleucina/genética , Sistema Urinário/anormalidades , Refluxo Vesicoureteral/genética , Animais , Anormalidades Congênitas/genética , Modelos Animais de Doenças , Feminino , Genes Recessivos , Humanos , Nefropatias/congênito , Nefropatias/genética , Masculino , Camundongos , Camundongos Mutantes , Anormalidades Urogenitais
13.
Kidney Int ; 85(6): 1429-33, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24429398

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.


Assuntos
Genes Dominantes , Mutação , Refluxo Vesicoureteral/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Hereditariedade , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Anormalidades Urogenitais
14.
Kidney Int ; 85(6): 1310-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24152966

RESUMO

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.


Assuntos
Canal Anal/anormalidades , Análise Mutacional de DNA , Esôfago/anormalidades , Exossomos , Testes Genéticos , Proteínas de Choque Térmico HSP90 , Cardiopatias Congênitas/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Mutação , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Refluxo Vesicoureteral/genética , Fatores Etários , Animais , Análise Mutacional de DNA/métodos , Europa (Continente) , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Testes Genéticos/métodos , Idade Gestacional , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Rim/embriologia , Rim/metabolismo , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Camundongos , Reação em Cadeia da Polimerase Multiplex , Linhagem , Valor Preditivo dos Testes , Fatores de Risco , Estados Unidos , Anormalidades Urogenitais , Refluxo Vesicoureteral/diagnóstico
15.
Birth Defects Res A Clin Mol Teratol ; 100(10): 750-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25131394

RESUMO

BACKGROUND: The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association. METHODS: We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features). RESULTS: We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range. CONCLUSION: Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.


Assuntos
Canal Anal/anormalidades , Criptorquidismo/genética , Esôfago/anormalidades , Fator 8 de Crescimento de Fibroblasto/genética , Cardiopatias Congênitas/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Mutação/genética , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Hormônio Antimülleriano/sangue , Sequência de Bases , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Hormônio Foliculoestimulante/sangue , Componentes do Gene , Alemanha , Heterozigoto , Humanos , Inibinas/sangue , Hormônio Luteinizante/sangue , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Testosterona/sangue
16.
Health Sci Rep ; 7(3): e1935, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38524771

RESUMO

Background: Congenital lower urinary tract obstruction (LUTO) describes a heterogeneous group of congenital malformations. Posterior urethral valves (PUV) represent the most common entity. Familial occurrence has been described, suggestive of underlying genetic factors. LUTO can occur in various degrees of severity. In severe forms, oligohydramnios, pulmonary hypoplasia, and renal damage can occur resulting in high pre- and postnatal mortality. On the contrary, mild forms may become apparent through recurrent urinary tract infections. Such high phenotypic variability has been described even within the same family. Here, we systematically screened parents of affected children for symptoms of LUTO. Methods: The study population consisted of parents of LUTO patients. Fathers over 50 years of age were excluded, to avoid inclusion of male phenocopies due to early prostatic hypertrophy. Uroflowmetry, ultrasonography for residual urine and hydronephrosis, and laboratory examination of standard renal retention parameters were assessed, and a detailed patient history was taken, including the assessment of the International Prostate Symptom Score. Results: Twenty-nine of 42 LUTO families enrolled were found eligible for the present study. Of these, we identified five families in which the father had already been diagnosed with infravesical obstruction (17%). Of the remaining families, nine agreed to participate in our study. Of these nine families, eight families had a child affected with PUV and one family had a child with urethral stenosis. Here, we found two fathers and one mother with symptoms of LUTO suggestive of mild LUTO and one family, in which the unborn male fetal brother of the affected index patient was also diagnosed prenatally with LUTO. Conclusion: Our observations suggest that LUTOs have a higher heritability than previously thought and that first-degree relatives of the affected should be clinically assessed for symptoms of LUTO.

17.
J Clin Med ; 13(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38930106

RESUMO

Background: Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods: This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients' demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results: Fifty-seven patients were analyzed with a median age of 15 years (range, 7-18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0-23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions: AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.

18.
Cells ; 13(2)2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38247840

RESUMO

Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1-/- embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1-/- embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs.


Assuntos
Quilotórax , Animais , Feminino , Humanos , Camundongos , Gravidez , Quilotórax/genética , Feto , Doenças Genéticas Ligadas ao Cromossomo X , Hidropisia Fetal , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout
19.
Mol Cell Pediatr ; 10(1): 2, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36977792

RESUMO

Advances in molecular biology are improving our understanding of the genetic causes underlying human congenital lower urinary tract (i.e., bladder and urethral) malformations. This has recently led to the identification of the first disease-causing variants in the gene BNC2 for isolated lower urinary tract anatomical obstruction (LUTO), and of WNT3 and SLC20A1 as genes implicated in the pathogenesis of the group of conditions called bladder-exstrophy-epispadias complex (BEEC). Implicating candidate genes from human genetic data requires evidence of their influence on lower urinary tract development and evidence of the found genetic variants' pathogenicity. The zebrafish (Danio rerio) has many advantages for use as a vertebrate model organism for the lower urinary tract. Rapid reproduction with numerous offspring, comparable anatomical kidney and lower urinary tract homology, and easy genetic manipulability by Morpholino®-based knockdown or CRISPR/Cas editing are among its advantages. In addition, established marker staining for well-known molecules involved in urinary tract development using whole-mount in situ hybridization (WISH) and the usage of transgenic lines expressing fluorescent protein under a tissue-specific promoter allow easy visualization of phenotypic abnormalities of genetically modified zebrafish. Assays to examine the functionality of the excretory organs can also be modeled in vivo with the zebrafish. The approach of using these multiple techniques in zebrafish not only enables rapid and efficient investigation of candidate genes for lower urinary tract malformations derived from human data, but also cautiously allows transferability of causality from a non-mammalian vertebrate to humans.

20.
Biomolecules ; 13(7)2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37509153

RESUMO

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well. METHODS: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2. RESULTS: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (NR1H2, GKAP1), four candidate genes with autosomal-recessive biallelic variants (AKR1B10, CLSTN3, NDST4, PLEKHB1) and one candidate gene with suggestive uniparental disomy (SVEP1). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68). CONCLUSIONS: According to previous studies, our study further implicates LZTR1 in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.


Assuntos
Extrofia Vesical , Epispadia , Masculino , Humanos , Extrofia Vesical/genética , Epispadia/genética , Exoma/genética , Bexiga Urinária/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Membrana/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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