Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Molluscum Contagiosum/pathology , Molluscum contagiosum virus/pathogenicity , Nuclear Proteins/metabolism , Skin/pathology , Transcription Factors/metabolism , Case-Control Studies , Cell Cycle Proteins , Humans , Molluscum Contagiosum/virology , Protein Serine-Threonine Kinases/metabolism , Skin/virology , Trans-Activators , Transcriptional Coactivator with PDZ-Binding Motif ProteinsABSTRACT
A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late-onset adrenal insufficiency without hypogonadism.
Subject(s)
Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/genetics , DAX-1 Orphan Nuclear Receptor/genetics , Genetic Association Studies , Mutation, Missense , Adult , Age of Onset , Alleles , Amino Acid Substitution , Biomarkers , DAX-1 Orphan Nuclear Receptor/chemistry , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Genotype , Humans , Male , Models, Molecular , Pedigree , Protein Conformation , Exome SequencingABSTRACT
Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude â¼500 arRP mutations in â¼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.