RESUMO
Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.
Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/metabolismo , Mutação , Proteínas de Neoplasias/metabolismo , Proteínas/genética , Proteínas/metabolismo , Antígenos de Neoplasias/genética , Ataxia/genética , Proteínas de Ciclo Celular , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Mapeamento Cromossômico , Cromossomos Humanos Par 4 , Cílios/genética , Estudos de Coortes , Consanguinidade , Proteínas do Citoesqueleto , Éxons , Marcadores Genéticos , Haplótipos , Homozigoto , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/genética , Masculino , Repetições de Microssatélites , Hipotonia Muscular/genética , Proteínas de Neoplasias/genética , Transtornos da Motilidade Ocular/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Radiografia , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Síndrome , Técnicas do Sistema de Duplo-HíbridoRESUMO
CONTEXT: Whether 100% fruit juice consumption causes weight gain in children remains controversial. OBJECTIVE: To determine the association between 100% fruit juice consumption and change in BMI or BMI z score in children. DATA SOURCES: PubMed, Embase, CINAHL, and Cochrane databases. STUDY SELECTION: Longitudinal studies examining the association of 100% fruit juice and change in BMI measures were included. DATA EXTRACTION: Two independent reviewers extracted data using a predesigned data collection form. RESULTS: Of the 4657 articles screened, 8 prospective cohort studies (n = 34 470 individual children) met the inclusion criteria. Controlling for total energy intake, 1 daily 6- to 8-oz serving increment of 100% fruit juice was associated with a 0.003 (95% CI: 0.001 to 0.004) unit increase in BMI z score over 1 year in children of all ages (0% increase in BMI percentile). In children ages 1 to 6 years, 1 serving increment was associated with a 0.087 (95% confidence interval: 0.008 to 0.167) unit increase in BMI z score (4% increase in BMI percentile). 100% fruit juice consumption was not associated with BMI z score increase in children ages 7 to 18 years. LIMITATIONS: All observational studies; studies differed in exposure assessment and covariate adjustment. CONCLUSIONS: Consumption of 100% fruit juice is associated with a small amount of weight gain in children ages 1 to 6 years that is not clinically significant, and is not associated with weight gain in children ages 7 to 18 years. More studies are needed in children ages 1 to 6 years.