RESUMO
Anomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2(-/-) female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C>A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis.
Assuntos
Mutação , Insuficiência Ovariana Primária/genética , Proteínas Repressoras/genética , Transativadores/genética , Adulto , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
FOXO4 constitutes a coherent candidate gene associated with premature ovarian failure (POF) pathogenesis. This study sequenced the coding and exon-flanking regions of this gene in a panel of 116 POF patients and 143 controls of Tunisian origin. In both groups, the IVS2 + 41T > G sequence variant was identified. It is concluded that coding mutations of FOXO4 should not be a common cause of the disease in women from the Tunisian population. However, this study cannot exclude that FOXO4 dysfunctions, originated from open reading frame or promoter sequence variations, might be associated with the pathogenesis of the disease in other ethnical groups.
Assuntos
Mutação , Insuficiência Ovariana Primária/genética , Fatores de Transcrição/genética , Adulto , Proteínas de Ciclo Celular , Análise Mutacional de DNA , Feminino , Fatores de Transcrição Forkhead , Frequência do Gene , Humanos , Fases de Leitura Aberta , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Fatores de Transcrição/química , TunísiaRESUMO
Earlier reports demonstrated a key role of Cdkn1b during mouse ovarian development. In this study, the sequencing analysis of the complete coding region of this gene in a panel of premature ovarian failure patients and control subjects reveals a novel mutation potentially related to the phenotype.