Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients.

Mutations of the transcription factor FOXL2, involved in cranio-facial and ovarian development lead to the Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) in human. Here, we describe nine mutations in the open reading frame of FOXL2. Six of them are novel: c.292T>A (p.Trp98Arg), c.323T>C (p.Leu108Pro), c.650C>G (p.Ser217Cys) and three frameshifts. We have performed localization and functional studies for three of them. We have observed a strong cytoplasmic mislocalization induced by the missense mutation p.Leu108Pro located in the forkhead (FKH) domain of FOXL2. In line with this, transcriptional activity assays confirmed the loss-of-function induced by this variant. Interestingly, the novel mutation p.Ser217Cys, mapping between the FKH and the polyalanine domain of FOXL2 and producing a mild eyelid phenotype, led to normal localization and transactivation. We have also modeled the structure of the FKH domain to explore the potential structural impact of the mutations reported here and other previously reported ones. This analysis shows that mutants can be sorted into two classes: those that potentially alter protein-protein interactions and those that might disrupt the interactions with DNA. Our findings reveal new insights into the molecular effects of FOXL2 mutations, especially those affecting the FKH binding domain. (c) 2008 Wiley-Liss, Inc.

A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.

The blepharophimosis syndrome (BPES) is an autosomal dominant developmental disorder in which craniofacial/eyelid malformations are associated (type I) or not (type II) with premature ovarian failure (POF). Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for both types of BPES. Heterozygous polyalanine expansions of +10 residues (FOXL2-Ala24) account for 30% of FOXL2 mutations and are fully penetrant for the eyelid phenotype. Here we describe the first homozygous FOXL2 mutation leading to a polyalanine expansion of +5 residues (FOXL2-Ala19). This novel mutation segregates in an Indian family where heterozygous mutation carriers are unaffected whereas homozygous individuals have the typical BPES phenotype, with proven POF in one female. Expression of the FOXL2-Ala19 protein in COS-7 cells revealed a significantly higher cytoplasmic retention compared to the wild-type protein. This is the first study providing genetic evidence for a recessive inheritance of BPES associated with ovarian dysfunction.

Spectrum and the susceptibilities of microbial isolates in cases of congenital nasolacrimal duct obstruction.

PURPOSE: To determine the microbial profile of congenital nasolacrimal duct obstruction (CNLDO) and the appropriate antimicrobial agents based on the sensitivity pattern of the isolated microorganisms. METHODS: Two hundred thirty-eight eyes of 187 young children in the age group of 0-5 years with CNLDO were included in the study. A group of 40 children (80 eyes) who had attended the hospital for other ocular disorders was considered a control. Material obtained from the lacrimal sac was cultured, and infectious agents were isolated. Susceptibility testing was done by Kirby-Bauer disk diffusion method for 7 different antibiotics. Fisher's exact test was used to look for statistical associations between the age group, the type of discharge, and the type of microorganisms isolated. RESULTS: Of the 238 samples with a clinical diagnosis of CNLDO, 197 (83%) yielded a positive culture. There was no growth in 41 samples (17%). Altogether, there were 217 isolates. One hundred twenty-four (57%) isolates were Gram-positive bacteria, the most frequent isolate being Streptococcus pneumoniae. Gram-negative bacteria accounted for 93 (43%) of the isolates, the most frequent isolate being Haemophilus influenza. There was one fungal isolate (0.5%) of Candida tropicalis. Gram-positive bacteria were sensitive to chloramphenicol, vancomycin, and ofloxacin and Gram-negative bacteria to ofloxacin and ciprofloxacin. CONCLUSIONS: Chronic dacryocystitis caused by CNLDO is associated with an almost-equal proportion of Gram-positive and Gram-negative bacteria. Ofloxacin topical drops can be used in the treatment of cases with CNLDO.

Presumed trematode-induced granulomatous anterior uveitis: a newly recognized cause of intraocular inflammation in children from south India.

PURPOSE: To describe the epidemiologic, clinical, and histopathologic features of a presumed trematode granulomatous anterior uveitis, primarily in children from south India. DESIGN: Prospective, noncomparative, case series. METHODS: Children with clinical evidence of granulomatous anterior uveitis were selected for the study. Those who presented with distinct anterior chamber nodules were evaluated. Demographic details, such as clinical findings and course of illness, were noted. Patients underwent either medical treatment or surgical aspiration of the lesion based on the size of the lesion. Aspirated materials were subjected to histopathologic analysis and cultures for bacteria and fungi. Response to treatment and final visual status were evaluated. RESULTS: One hundred thirteen patients with anterior chamber nodules were seen between 1998 and 2000. Ninety-three (82.4%) were males and 20 (17.7%) were females. The median age was 11.0 years. All patients were from south India and all gave a history of bathing or swimming in the local pond or river. All had normal systemic work ups. Of the 113 patients, 110 had anterior chamber nodules and three had both anterior chamber and subconjunctival nodules. Aspirates of the anterior chamber lesions revealed lymphocytes, intact and necrotic neutrophils, and eosinophils admixed with histiocytes. One subconjunctival nodule showed necrotizing granuloma, displaying the tegument of a trematode. Those patients who were followed had good visual recovery after medical or surgical intervention or both. CONCLUSION: The present study shows a newly recognized granulomatous anterior uveitis caused by a presumed water-borne trematode infection. This infection appears to be a common cause of pediatric granulomatous anterior uveitis in south India.