RESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
Assuntos
Proteínas de Ligação a DNA/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Mutação , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sistema Urinário/metabolismo , Anormalidades Urogenitais/genética , Proteínas de Anfíbios/antagonistas & inibidores , Proteínas de Anfíbios/genética , Proteínas de Anfíbios/metabolismo , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Família , Feminino , Fatores de Transcrição Forkhead/metabolismo , Heterozigoto , Humanos , Lactente , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfolinos/genética , Morfolinos/metabolismo , Linhagem , Ligação Proteica , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Sistema Urinário/anormalidades , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/patologia , Sequenciamento do Exoma , XenopusRESUMO
We present the case of a patient of Macedonian origin with unilateral renal agenesis and ureterovesical junction obstruction in combination with further abnormalities including midface hypoplasia, scoliosis as well as camptodactyly of one toe. Whole-exome sequencing analysis revealed compound heterozygous variants in the FAT4 gene. Recessive variants in FAT4 are a known cause of van Maldergem syndrome (VMS) in which congenital anomalies of the kidney and urinary tract are a less characteristic but common feature. The initial presentation of our patient was not clinically recognizable. However, in view of the molecular findings, the most likely diagnosis is a mild manifestation of VMS. Only very few publications have reported patients with VMS and mutations in FAT4 to date. With this case, we hope to provide further insight into the phenotypic variability of this syndrome.