ABSTRACT
El síndrome WAGR (tumor de Wilms, aniridia, anomalías genitourinarias y retraso mental) es un trastorno genético infrecuente debido a la deleción de la región 11p13, que contiene los genes WT1 y PAX6. Comprende una combinación distintiva de afecciones clínicas; la aniridia y el tumor de Wilms son las más notables. Se presenta a un lactante de 17 meses con microcefalia, alteraciones oculares (buftalmos, leucocoria, aniridia bilateral), hipoplasia escrotal, testículos en la región inguinal y retraso en el neurodesarrollo, a quien se le realizó el estudio de amplificación de sondas dependiente de ligandos múltiples para WT1, que mostró haploinsuficiencia en las sondas que hibridaban la región 11p13, compatible con una deleción en heterocigosis del gen. Posteriormente, se diagnosticó tumor de Wilms. Dada su baja prevalencia, es importante difundir sus características clínicas y hacer énfasis en un manejo interdisciplinario centrado en la identificación precoz del síndrome y de sus posibles complicaciones. .
WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) is an uncommon genetic disorder due to the deletion of the 11p13 region that contains the WT1 and PAX6 genes. It involves a distinctive combination of clinical conditions, with aniridia and Wilms tumor being the most notable. We present a 17-month-old infant with microcephaly, ocular alterations (buphthalmos, leukocoria, bilateral aniridia), scrotal hypoplasia, undescended testes and neurodevelopmental delay who underwent multiplex ligation-dependent probe amplification study for WT1, showing haploinsufficiency in the probes that hybridize to the 11p13 region, compatible with an heterozygous deletion of the gene. Wilms tumor was later diagnosed. WAGR syndrome is infrequent; its report in Latin America is low. It is important to disseminate its clinical characteristics, emphasizing an interdisciplinary management focused on the early identification of both the syndrome and its possible complications.
Subject(s)
Humans , Male , Infant , WAGR Syndrome/genetics , Wilms Tumor , Urogenital Abnormalities , Aniridia , WAGR Syndrome/metabolism , WT1 ProteinsABSTRACT
BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined. CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions. CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Hormones/metabolism , Sequence Deletion , WAGR Syndrome/metabolism , Child, Preschool , Comparative Genomic Hybridization , DNA Methylation , Epigenesis, Genetic , Female , Humans , Hypoglycemia , WAGR Syndrome/genetics , WAGR Syndrome/physiopathologyABSTRACT
AGR syndrome (the clinical triad of aniridia, genitourinary anomalies, and mental retardation, a subgroup of WAGR syndrome for Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation) is a rare syndrome caused by a contiguous gene deletion in the 11p13-14 region. However, the mechanisms of WAGR syndrome pathogenesis are elusive. In this study we provide evidence that LGR4 (also named GPR48), the only G-protein-coupled receptor gene in the human chromosome 11p12-11p14.4 fragment, is the key gene responsible for the diseases of AGR syndrome. Deletion of Lgr4 in mouse led to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Furthermore, Lgr4 inactivation significantly increased cell apoptosis and decreased the expression of multiple important genes involved in the development of WAGR syndrome related organs. Specifically, deletion of Lgr4 down-regulated the expression of histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways both in mouse embryonic fibroblast cells and in urinary and reproductive system mouse tissues. Our data suggest that Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome.
Subject(s)
Gene Deletion , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/genetics , WAGR Syndrome/genetics , Animals , Anxiety/genetics , Cell Line , Chromosomes, Human, Pair 11/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Epigenesis, Genetic/genetics , F-Box Proteins/metabolism , Female , Gene Expression Regulation/genetics , Histone Demethylases/genetics , Histone Demethylases/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/metabolism , Learning , Male , Mice , Organ Specificity , Receptors, G-Protein-Coupled/metabolism , Transcription, Genetic/genetics , WAGR Syndrome/metabolism , WAGR Syndrome/physiopathology , WAGR Syndrome/psychologyABSTRACT
A novel leucine-zipper gene, leucine zipper protein 2 (Luzp2), has been cloned as part of an aberrant deletion-fusion transcript in the chromosomal interval between Gas2 and Herc2 on mouse Chromosome 7 (Chr 7). Luzp2 is normally expressed only in brain and spinal cord. The human homolog of Luzp2 maps to Chr 11p13-11p14 by radiation-hybrid mapping and is deleted in some patients with Wilms tumor-Aniridia-Genitourinary anomalies-mental Retardation (WAGR) syndrome. Disruption of Luzp2 by gene targeting in mice did not result in any obvious abnormal phenotypes.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 11/genetics , DNA-Binding Proteins/genetics , Leucine Zippers/genetics , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Chromosome Deletion , Cloning, Molecular , DNA Mutational Analysis , DNA Primers/chemistry , DNA-Binding Proteins/isolation & purification , DNA-Binding Proteins/metabolism , Female , Gene Expression Regulation, Developmental , Gene Targeting , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Phenotype , Polymerase Chain Reaction , Radiation Hybrid Mapping , Ribonuclease, Pancreatic/metabolism , Tumor Cells, Cultured , WAGR Syndrome/genetics , WAGR Syndrome/metabolismABSTRACT
WAGR syndrome is an acronym for a rare constellation of congenital abnormalities including predisposition to Wilms' tumor, Aniridia, Genitourinary malformations, and mental Retardation. These congenital defects are associated with a constitutional deletion affecting one copy of chromosome band 11p13, implicating the loss of one allele from a number of contiguous genes in this syndrome. Predisposition to Wilms' tumor and genitourinary abnormalities have been attributed to hemizygosity for the WT1 tumor suppressor gene, a transcriptional repressor that is normally expressed transiently during kidney development. Here we show that a Wilms' tumor arising in a child with WAGR syndrome contained a point mutation within the remaining WT1 allele. This mutation resulted in a glycine to aspartic acid substitution within the putative trans-activation domain of WT1, converting the encoded protein from a transcriptional repressor to an activator of its target DNA sequence. Thus, a critical amino acid substitution can alter the functional properties of WT1 and provide the "second hit" required for Wilms tumorigenesis.
