WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature.

Mutations in the WDR45 gene have been identified as causative for the only X-linked type of neurodegeneration with brain iron accumulation (NBIA), clinically characterized by global developmental delay in childhood, followed by a secondary neurological decline with parkinsonism and/or dementia in adolescence or early adulthood. Recent reports suggest that WDR45 mutations are associated with a broader phenotypic spectrum. We identified a novel splice site mutation (c.440-2 A > G) in a 5-year-old Argentinian patient with Rett-like syndrome, exhibiting developmental delay, microcephaly, seizures and stereotypic hand movements, and discuss this finding, together with a review of the literature. Additional patients with a clinical diagnosis of Rett (-like) syndrome were also found to carry WDR45 mutations before (or without) clinical decline or signs of iron accumulation by magnetic resonance imaging (MRI). This information indicates that WDR45 mutations should be added to the growing list of genetic alterations linked to Rett-like syndrome. Further, clinical symptoms associated with WDR45 mutations ranged from early-onset epileptic encephalopathy in a male patient with a deletion of WDR45 to only mild cognitive delay in a female patient, suggesting that analysis of this gene should be considered more often in patients with developmental delay, regardless of severity. The increasing use of next generation sequencing technologies as well as longitudinal follow-up of patients with an early diagnosis will help to gain additional insight into the phenotypic spectrum associated with WDR45 mutations.

Vibrio cholerae cytolysin is essential for high enterotoxicity and apoptosis induction produced by a cholera toxin gene-negative V. cholerae non-O1, non-O139 strain.

Cholera toxin (CT) gene-negative Vibrio cholerae non-O1, non-O139 strains may cause severe diarrhea though their pathogenic mechanism remains unclear. V. cholerae cytolysin (VCC) is a pore-forming exotoxin encoded in the hlyA gene of V. cholerae whose contribution to the pathogenesis is not fully understood. In this work, the virulence properties of a CT gene-negative V. cholerae non-O1, non-O139 strain causing a cholera-like syndrome were analyzed. Inoculation of rabbit ileal loops with the wild type strain induced extensive fluid accumulation, accompanied by severe histopathological damage characterized by villus shortening, lymphangiectasia and focal areas of necrosis. These pathogenic effects were abrogated by mutation of the hlyA gene thus pointing out the main role of VCC in the virulence of the strain. Interestingly, this toxin was capable of triggering apoptosis in human intestinal cell lines due to its anion channel activity. Moreover, the wild type strain also induced increased apoptosis of the intestinal epithelium cells which was not observed upon inoculation of the VCC null mutant strain, indicating that VCC may trigger apoptotic cell death during infection in vivo. Altogether, these results support a main role of VCC in the pathogenesis of the CT gene-negative V. cholerae non-O1, non-O139 strain and identify apoptosis as a previously unrecognized cell death pathway triggered by VCC.

Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities.

PURPOSE: The PITX3 gene, which codes for a homeobox bicoidlike transcription factor is responsible for dominant cataract and anterior segment mesenchymal dysgenesis in humans. In the current study, a family with autosomal dominant posterior polar cataract (PPC) and a PITX3 mutation that cosegregates with the disease was examined. Also studied were two siblings who were homozygous for the PITX3 mutation who had microphthalmia and significant neurologic impairment. METHODS: A genome-wide screen, linkage analysis in the PITX3 chromosomal region 10q25, haplotype analysis, and sequencing of the PITX3 gene were performed on 28 affected and 14 unaffected member of a three-generation Lebanese family. RESULTS: Genome-wide linkage analysis showed a lod score of 3.56 at theta = 0.00 on chromosome 10 at area q25. Analysis of the haplotypes and phenotypes confined the disease locus to a region on 10q25 between the markers D10S1239 and D10S1268. A candidate gene, PITX3, maps to that region. Sequencing of the PITX3 gene revealed a heterozygous G deletion mutation in 25 of the 42 family members. In addition, two siblings from a consanguineous marriage were found to be homozygous for the deletion. CONCLUSIONS: This is the first report of homozygous PITX3 mutations in humans. The phenotype in these individuals highlights the role of PITX3 in ocular and central nervous system (CNS) development.

Of mice and men: tyrosinase modification of congenital glaucoma in mice but not in humans.

PURPOSE: Primary congenital glaucoma (PCG) is an autosomal recessive ocular trait caused by mutations in the gene for cytochrome P4501B1 (CYP1B1). Although PCG is often considered to be fully penetrant, the disease shows 50% penetrance in some Saudi Arabian families. The familial segregation of the nonpenetrance suggests a genetic modifier. Recently, tyrosinase (Tyr) deficiency was found to worsen the drainage structure/ocular dysgenesis phenotype of Cyp1b1-/- mice, suggesting that Tyr is a modifier of the phenotype. In the current study, tyrosinase (TYR) was investigated in human PCG. METHODS: A genome-wide screen, a single nucleotide polymorphism (SNP) analysis in the TYR chromosomal region 11q13-q21, and sequencing of the TYR gene was performed with individuals from Saudi Arabian families with multiple, clinically confirmed, molecularly proven, nonpenetrant members. RESULTS: The study outcome did not support TYR as a modifier of the PCG phenotype in this population. The sequencing data showed no TYR mutations in the nonpenetrant family members and no difference in polymorphism frequencies between nonpenetrant or fully penetrant families. CONCLUSIONS: TYR is not a modifier of the CYP1B1-associated PCG phenotype in the Saudi Arabian population.