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1.
Physiol Genomics ; 52(1): 56-70, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841396

RESUMO

The HSRA rat is a model of congenital abnormalities of the kidney and urogenital tract (CAKUT). Our laboratory has used this model to investigate the role of nephron number (functional unit of the kidney) in susceptibility to develop kidney disease as 50-75% offspring are born with a single kidney (HSRA-S), while 25-50% are born with two kidneys (HSRA-C). HSRA-S rats develop increased kidney injury and hypertension with age compared with nephrectomized two-kidney animals (HSRA-UNX), suggesting that even slight differences in nephron number can be an important driver in decline in kidney function. The HSRA rat was selected and inbred from a family of outbred heterogeneous stock (NIH-HS) rats that exhibited a high incidence of CAKUT. The HS model was originally developed from eight inbred strains (ACI, BN, BUF, F344, M520, MR, WKY, and WN). The genetic make-up of the HSRA is therefore a mosaic of these eight inbred strains. Interestingly, the ACI progenitor of the HS model exhibits CAKUT in 10-15% of offspring with the genetic cause being attributed to the presence of a long-term repeat (LTR) within exon 1 of the c-Kit gene. Our hypothesis is that the HSRA and ACI share this common genetic cause, but other alleles in the HSRA genome contribute to the increased penetrance of CAKUT (75% HSRA vs. 15% in ACI). To facilitate genetic studies and better characterize the model, we sequenced the whole genome of the HSRA to a depth of ~50×. A genome-wide variant analysis of high-impact variants identified a number of novel genes that could be linked to CAKUT in the HSRA model. In summary, the identification of new genes/modifiers that lead to CAKUT/loss of one kidney in the HSRA model will provide greater insight into association between kidney development and susceptibility to develop cardiovascular disease later in life.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Néfrons/embriologia , Organogênese/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Sequenciamento Completo do Genoma , Animais , Sequência de Bases , Cromossomos de Mamíferos/genética , Modelos Animais de Doenças , Genoma , Genoma Mitocondrial , Íntrons/genética , Mitocôndrias/genética , Filogenia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos
2.
J Am Soc Nephrol ; 31(1): 139-147, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862704

RESUMO

BACKGROUND: Researchers have identified about 40 genes with mutations that result in the most common cause of CKD in children, congenital anomalies of the kidney and urinary tract (CAKUT), but approximately 85% of patients with CAKUT lack mutations in these genes. The anomalies that comprise CAKUT are clinically heterogenous, and thought to be caused by disturbances at different points in kidney development. However, identification of novel CAKUT-causing genes remains difficult because of their variable expressivity, incomplete penetrance, and heterogeneity. METHODS: We investigated two generations of a family that included two siblings with CAKUT. Although the parents and another child were healthy, the two affected siblings presented the same manifestations, unilateral renal agenesis and contralateral renal hypoplasia. To search for a novel causative gene of CAKUT, we performed whole-exome and whole-genome sequencing of DNA from the family members. We also generated two lines of genetically modified mice with a gene deletion present only in the affected siblings, and performed immunohistochemical and phenotypic analyses of these mice. RESULTS: We found that the affected siblings, but not healthy family members, had a homozygous deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 (CBWD1) gene. Whole-genome sequencing uncovered genomic breakpoints, which involved exon 1 of CBWD1, harboring the initiating codon. Immunohistochemical analysis revealed high expression of Cbwd1 in the nuclei of the ureteric bud cells in the developing kidneys. Cbwd1-deficient mice showed CAKUT phenotypes, including hydronephrosis, hydroureters, and duplicated ureters. CONCLUSIONS: The identification of a deletion in CBWD1 gene in two siblings with CAKUT implies a role for CBWD1 in the etiology of some cases of CAKUT.


Assuntos
Deleção de Genes , Transferases de Grupos Nitrogenados/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem
3.
Am J Hum Genet ; 106(1): 121-128, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883643

RESUMO

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.


Assuntos
Anormalidades Múltiplas/patologia , Transtornos do Desenvolvimento Sexual/patologia , Holoprosencefalia/patologia , Mutação , Fosfatase de Miosina-de-Cadeia-Leve/genética , Anormalidades Urogenitais/patologia , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/genética , Feminino , Idade Gestacional , Holoprosencefalia/genética , Humanos , Masculino , Fenótipo , Gravidez , Anormalidades Urogenitais/genética
4.
Am J Hum Genet ; 105(6): 1286-1293, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31708116

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.


Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Rim/anormalidades , Mutação , Receptores Nicotínicos/genética , Sistema Urinário/anormalidades , Anormalidades Urogenitais/etiologia , Adulto , Doenças do Sistema Nervoso Autônomo/genética , Doenças do Sistema Nervoso Autônomo/patologia , Feminino , Seguimentos , Humanos , Rim/patologia , Masculino , Linhagem , Prognóstico , Sistema Urinário/patologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Adulto Jovem
5.
Taiwan J Obstet Gynecol ; 58(6): 859-863, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759543

RESUMO

OBJECTIVE: We present detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound. CASE REPORT: A 37-year-old, primigravid woman was referred for level II ultrasound examination at 16 weeks of gestation because of oligohydramnios. The parents were phenotypically normal, and there were no congenital malformations in the family. Prenatal ultrasound at 17 weeks of gestation revealed a fetus with fetal growth biometry equivalent to 16 weeks, oligohydramnios with an amniotic fluid index (AFI) of 1.4 cm and bilateral renal dysplasia without sonographic demonstration of bilateral renal arteries. The pregnancy was subsequently terminated, and a 137-g fetus was delivered without characteristic facial dysmorphism. Postnatal cytogenetic analysis of the umbilical cord and parental bloods revealed normal karyotypes. However, array comparative genomic hybridization (aCGH) analysis on the DNA extracted from the umbilical cord revealed a 2.038-Mb microdeletion of 1q21.1-q21.2 encompassing 11 [Online Mendelian Inheritance in Man (OMIM)] genes of PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, GPR89B, NBPF14, TRN-GTT2-1 and NBPF20. The mother was found to carry the same microdeletion. A missense mutation of c.2353T > G, p.Ser785Ala in CHD1L was detected in the umbilical cord. The father was found to carry a heterozygous mutation of c.2353T > G, p.Ser785Ala in CHD1L. CONCLUSION: Fetuses with a 1q21.1 microdeletion and concomitant CHD1L mutation may present oligohydramnios and bilateral renal dysplasia on prenatal ultrasound.


Assuntos
Anormalidades Múltiplas/diagnóstico , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Túbulos Renais Proximais/anormalidades , Megalencefalia/diagnóstico , Mutação de Sentido Incorreto , Oligo-Hidrâmnio/diagnóstico , Ultrassonografia Pré-Natal/métodos , Anormalidades Urogenitais/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , DNA/genética , DNA Helicases/metabolismo , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Megalencefalia/genética , Megalencefalia/metabolismo , Oligo-Hidrâmnio/genética , Gravidez , Anormalidades Urogenitais/genética
7.
Nature ; 574(7777): 249-253, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578523

RESUMO

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Epiderme/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células Epidérmicas/metabolismo , Epiderme/embriologia , Anormalidades do Olho/genética , Feminino , Dedos/anormalidades , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Joelho/anormalidades , Articulação do Joelho/anormalidades , Lábio/anormalidades , Metabolismo dos Lipídeos/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Anormalidades Urogenitais/genética
8.
J Pathol ; 249(4): 472-484, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31400222

RESUMO

Transforming growth factor-ß (TGFß) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFß levels actually perturb ureter development. We therefore hypothesised that TGFß has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGFß ligands, as well as Tgfbr1 and Tgfbr2 coding for TGFß receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGFß1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGFß1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGFß. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFß1. To assess whether an endogenous TGFß axis functions in developing ureters, embryonic day 15 explants were exposed to TGFß receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGFß effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFß1, again generating cocoon-like structures, and to TGFß receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFßRI and TGFßRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFß in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFß up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Morfogênese , Fator de Crescimento Transformador beta/metabolismo , Ureter/anormalidades , Ureter/metabolismo , Anormalidades Urogenitais/metabolismo , Urotélio/anormalidades , Urotélio/metabolismo , Animais , Diferenciação Celular , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Humanos , Camundongos , Técnicas de Cultura de Órgãos , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Ureter/efeitos dos fármacos , Anormalidades Urogenitais/genética , Urotélio/efeitos dos fármacos
9.
BMC Med Genet ; 20(1): 132, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366388

RESUMO

BACKGROUND: FOXL2 gene mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and may be associated with premature ovarian insufficiency (POI). Two types of BPES were described in the literature. BPES type 2 is a simple association of inherited developmental defects of the eyelid area, while in type 1 female patients additionally suffer from POI. The following case study is the first report of endocrine impairments typical for menopausal transition in young female with NG_012454.1:g.138665342G > A, c.223C > T p.(Leu75Phe), mutation in FOXL2 gene. This mutation has been reported in the literature before, however until now, it was never linked to BPES type 1. CASE PRESENTATION: An 18-year-old nulliparous woman suspected of secondary amenorrhea was referred to our Endocrinology Outpatient Clinic. Blood tests revealed decreased levels of AMH (anti-Mullerian hormone) and increased levels of gonadotropins, suggesting menopausal transition. Her past medical history was remarkable for several ophthalmic defects that has required surgical interventions. BPES syndrome had not been suspected before, although the patient had reported a similar phenotype occurring in her father, sister and half-sister. Venous blood samples were collected from the female proband and from her three family members. Whole-exome sequencing and deep amplicon sequencing were performed. A potential pathogenic variant in the FOXL2 gene was revealed. Namely, the c.223C > T p.(Leu75Phe) missense variant was detected. CONCLUSIONS: The authors found mutations, c.223C > T p.(Leu75Phe) in the FOXL2 gene in a young woman with hormonal disorders suggesting menopausal transition. These results indicate that the possibility of different phenotypes should be considered in patients with a similar genetic mutation.


Assuntos
Blefarofimose/genética , Proteína Forkhead Box L2/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação , Insuficiência Ovariana Primária/genética , Anormalidades da Pele/genética , Anormalidades Urogenitais/genética , Adolescente , Amenorreia , Blefarofimose/fisiopatologia , Pálpebras , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Hormônios/sangue , Humanos , Linhagem , Fenótipo , Insuficiência Ovariana Primária/fisiopatologia , Anormalidades da Pele/fisiopatologia , Síndrome , Anormalidades Urogenitais/fisiopatologia , Sequenciamento Completo do Exoma
11.
Genet Med ; 21(12): 2755-2764, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31263215

RESUMO

PURPOSE: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. METHODS: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. RESULTS: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. CONCLUSION: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.


Assuntos
Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Bases de Dados Genéticas , Modelos Animais de Doenças , Exoma/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/complicações , Rim/anormalidades , Rim/embriologia , Masculino , Néfrons/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sistema Urinário/embriologia , Sistema Urinário/metabolismo , Sequenciamento Completo do Exoma/métodos , Xenopus laevis/genética , Xenopus laevis/metabolismo , Adulto Jovem
12.
J Am Soc Nephrol ; 30(8): 1398-1411, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31300484

RESUMO

BACKGROUND: Studies in mice suggest that perturbations of the GDNF-Ret signaling pathway are a major genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT). Mutations in Sprouty1, an intracellular Ret inhibitor, results in supernumerary kidneys, megaureters, and hydronephrosis in mice. But the underlying molecular mechanisms involved and which structural domains are essential for Sprouty1 function are a matter of controversy, partly because studies have so far relied on ectopic overexpression of the gene in cell lines. A conserved N-terminal tyrosine has been frequently, but not always, identified as critical for the function of Sprouty1 in vitro. METHODS: We generated Sprouty1 knockin mice bearing a tyrosine-to-alanine substitution in position 53, corresponding to the conserved N-terminal tyrosine of Sprouty1. We characterized the development of the genitourinary systems in these mice via different methods, including the use of reporter mice expressing EGFP from the Ret locus, and whole-mount cytokeratin staining. RESULTS: Mice lacking this tyrosine grow ectopic ureteric buds that will ultimately form supernumerary kidneys, a phenotype indistinguishable to that of Sprouty1 knockout mice. Sprouty1 knockin mice also present megaureters and vesicoureteral reflux, caused by failure of ureters to separate from Wolffian ducts and migrate to their definitive position. CONCLUSIONS: Tyrosine 53 is absolutely necessary for Sprouty1 function during genitourinary development in mice.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Tirosina/genética , Sistema Urinário/embriologia , Alanina/genética , Animais , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Proteínas de Fluorescência Verde/metabolismo , Queratinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Fenótipo , Fosforilação , Domínios Proteicos , Proteínas Proto-Oncogênicas c-ret/genética , Ureter/anormalidades , Sistema Urinário/crescimento & desenvolvimento , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Ductos Mesonéfricos/metabolismo
13.
Clin Exp Nephrol ; 23(9): 1119-1129, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31131422

RESUMO

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.


Assuntos
Síndrome de Bartter/genética , Doenças do Sistema Nervoso Central/genética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Adolescente , Adulto , Síndrome de Bartter/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Predisposição Genética para Doença , Hereditariedade , Humanos , Lactente , Japão , Doenças Renais Císticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Linhagem , Fenótipo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Anormalidades Urogenitais/diagnóstico , Refluxo Vesicoureteral/diagnóstico
14.
Gene ; 706: 62-68, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31048069

RESUMO

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant entity characterized by eyelid malformations and caused by mutations in the forkhead box L2 (FOXL2) gene. Clinical and genetic analyses of large cohorts of BPES patients from different ethnic origins are important for a better characterization of FOXL2 mutational landscape. The purpose of this study is to describe the phenotypic features and the causal FOXL2 variants in a Mexican cohort of BPES patients. A total of 12 individuals with typical facial findings were included. Clinical evaluation included palpebral measurements and levator function assessment. The complete coding sequence of FOXL2 was amplified by PCR and subsequently analyzed by Sanger sequencing. A total of 11 distinct FOXL2 pathogenic variants were identified in our cohort (molecular diagnostic rate of 92%), including 5 novel mutations. Our results broaden the BPES-related mutational spectrum and supports considerable FOXL2 allelic heterogeneity in our population.


Assuntos
Blefarofimose/genética , Proteína Forkhead Box L2/genética , Anormalidades da Pele/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Blefarofimose/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Pálpebras/metabolismo , Feminino , Proteína Forkhead Box L2/fisiologia , Fatores de Transcrição Forkhead/genética , Humanos , Lactente , Recém-Nascido , Masculino , México , Pessoa de Meia-Idade , Mutação , Fenótipo , Anormalidades da Pele/fisiopatologia , Anormalidades Urogenitais/fisiopatologia
15.
Eur J Med Genet ; 62(7): 103668, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077882

RESUMO

Blepharophimosis, Ptosis, and Epicanthus inversus Syndrome (BPES) is caused by autosomal dominant mutations in FOXL2. There are two forms of BPES: type I (with primary ovarian insufficiency (POI)) and type II (without POI). Data are presented from a large cohort of 177 BPES probands. Diagnostic testing identified a wide range of mutations in 119 mutation-positive patients (including 38 novel mutations). Although FOXL2 mutations are distributed throughout the gene, over 50% were frameshift mutations within a hotspot region of the gene that can be detected using a single primer pair to provide a cost-effective and rapid screening method. There was a significant proportion of de novo cases in this study, although in 7% there may be undetected parental mosaicism. There was an excess of female compared to male probands and a highly significant bias in the parental original of inherited mutations, with 20/21 found to be paternal in origin (95%). This could be because BPES in a female is more likely to come to clinical attention and because there is a generalised and more widespread clinical effect on fertility, in addition to the established association with POI. This study demonstrates the importance of cascade screening and provides new information on inheritance and parental mosaicism in BPES which will aid genetic counselling and accurate risk management.


Assuntos
Blefarofimose/genética , Proteína Forkhead Box L2/genética , Herança Paterna , Anormalidades da Pele/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação
16.
Hum Mol Genet ; 28(14): 2395-2414, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31032853

RESUMO

Heterozygous missense mutations in several genes in the WNT5A signaling pathway cause autosomal dominant Robinow syndrome 1 (DRS1). Our objective was to clarify the functional impact of a missense mutation in WNT5A on the skeleton, one of the main affected tissues in RS. We delivered avian replication competent retroviruses (RCAS) containing human wild-type WNT5A (wtWNT5A), WNT5AC83S variant or GFP/AlkPO4 control genes to the chicken embryo limb. Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter and 200% wider than controls. In contrast, bone dimensions in wtWNT5A limbs were slightly affected (20% shorter, 25% wider) but ossification occurred on schedule. The dysmorphology of bones was established during cartilage differentiation. Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of disrupted planar cell polarity (PCP) mechanisms. Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability. Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted, compared to wtWNT5A. Thus, in the chicken and human, RS phenotypes are produced from the C83S mutation, even though the variant protein is less abundant than wtWNT5A. We conclude the variant protein has dominant-negative effects on chondrogenesis leading to limb abnormalities.


Assuntos
Condrócitos/citologia , Condrogênese , Anormalidades Craniofaciais/metabolismo , Nanismo/metabolismo , Extremidades/embriologia , Deformidades Congênitas dos Membros/metabolismo , Anormalidades Urogenitais/metabolismo , Proteína Wnt-5a/genética , Animais , Animais Geneticamente Modificados , Cartilagem/metabolismo , Polaridade Celular/fisiologia , Embrião de Galinha , Galinhas , Condrogênese/genética , Anormalidades Craniofaciais/genética , Modelos Animais de Doenças , Nanismo/genética , Células HEK293 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Deformidades Congênitas dos Membros/genética , Mutação de Sentido Incorreto , Fenótipo , Anormalidades Urogenitais/genética , Via de Sinalização Wnt , Proteína Wnt-5a/metabolismo
18.
Gynecol Endocrinol ; 35(9): 772-776, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30887870

RESUMO

Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene-gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Doenças Ósseas Metabólicas/genética , Glucuronidase/genética , Receptores de Calcitriol/genética , Síndrome de Turner/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Epistasia Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Rim/anormalidades , Redes e Vias Metabólicas/genética , México/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores de Calcitriol/metabolismo , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologia , Anormalidades Urogenitais/complicações , Anormalidades Urogenitais/epidemiologia , Vitamina D/metabolismo , Adulto Jovem
19.
Mil Med Res ; 6(1): 4, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30760330

RESUMO

BACKGROUND: Zinner syndrome represents a rare congenital malformation of the urinary tract. It comprises a constellation of Wolffian duct anomalies and is almost exclusively encountered as a classic triad of seminal vesicle cysts, ejaculatory duct obstruction and renal agenesis. Patients can be either asymptomatic or symptomatic. Recently, minimally invasive surgical techniques have emerged, superseding traditional surgery for select symptomatic cases. Our case highlights the finding of a rare clinical syndrome that was incidentally detected during a routine mass screening of military recruits in the Greek Armed Forces. CASE PRESENTATION: Herein, we present a case of a 19-year-old male who reported having a solitary right kidney when examined in a military training center of Northern Greece. No additional clinical information was available; thus, referral to a tertiary urology department for further investigation ensued. Imaging studies, namely, computed tomography and magnetic resonance imaging, revealed left renal aplasia, multiple left seminal vesicle cysts, and ejaculatory duct obstruction. Laboratory values and urinalysis were within normal range. Semen analysis was significant for cryptozoospermia. Our patient remained asymptomatic during the entire hospitalization. Long-term follow-up was recommended. Nevertheless, he declined further investigation and sought treatment in a private practice setting. CONCLUSIONS: This article aims to present the incidental diagnosis of a rare syndrome in a military setting. Population screening conducted in the armed forces permits the identification of undiagnosed diseases that warrant further investigation. To the best of our knowledge, this was the first report of Zinner syndrome in a military recruit and the second case cited of a Greek patient in the published literature. Regular follow-up is the key to timely intervention in conservatively managed cases.


Assuntos
Militares , Glândulas Seminais/anormalidades , Anormalidades Urogenitais/complicações , Anormalidades Congênitas/genética , Anormalidades Congênitas/fisiopatologia , Grécia , Humanos , Achados Incidentais , Rim/anormalidades , Rim/fisiopatologia , Masculino , Análise do Sêmen , Rim Único/complicações , Rim Único/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/fisiopatologia , Adulto Jovem
20.
Prenat Diagn ; 39(3): 165-174, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30650192

RESUMO

OBJECTIVE: To evaluate the usefulness and incremental diagnostic yield of chromosomal microarray analysis (CMA) compared with standard karyotyping in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: A prospective cohort study and systematic review of the literature were conducted. In the prospective cohort study, 123 fetuses with CAKUT, as detected by prenatal ultrasound at our center, were enrolled and evaluated using karyotyping and CMA. In the meta-analysis, articles in PubMed and ISI Web of Knowledge databases describing copy number variations (CNVs) in prenatal cases of CAKUT were included. RESULTS: Among the 123 fetuses in our prospective cohort study, 13 fetuses were detected with chromosomal abnormalities or submicroscopic chromosomal abnormalities by both karyotyping and CMA. In the remaining 110 fetuses, four pathogenic CNVs in four fetuses were only detected by CMA, indicating an excess diagnostic yield of 3.6%. Six publications and our own study met the inclusion criteria for the meta-analysis. In total, 615 fetuses with CAKUT were included. The pooled data from all of the reviewed studies indicate that the incremental yield of CMA over karyotyping was 3.8%. CONCLUSION: The use of CMA provides a 3.8% incremental yield of detecting pathogenic CNVs in fetuses with CAKUT and normal karyotype.


Assuntos
Aberrações Cromossômicas , Diagnóstico Pré-Natal/métodos , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Adulto , Feminino , Humanos , Análise em Microsséries , Gravidez , Estudos Prospectivos , Adulto Jovem
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