Molecular genetic investigation of a novel skeletal patterning disorder, x-linked absent radius spectrum (XLARS)

• Main Author: Campbell, Jennifer
• Published: University of Newcastle Upon Tyne 2012
• Subjects: 616.042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612621

Skeletal patterning disorders are a genetically heterogeneous group of congenital malformations, and may cause significant morbidity. X-linked limb reduction defects are rare. A family with a novel X-linked disorder characterised by absent radii and ulnae, hypoplastic thumbs, either short femora and tibiae or a single long bone in the lower limbs, and pelvic skeletal patterning abnormalities, is described. The disorder was mapped to a large interval on chromosome Xq. A second family, with an X-linked radial-ray deficiency, mapped to a smaller region located within the interval identified in Family 1, was identified from the literature. Sanger sequencing of coding exons of 9 candidate genes within the common mapped region, and subsequent exome sequencing of the entire X chromosome, failed to detect a pathogenic mutation in affected males from Family 1. Targeted resequencing of the larger interval, including coding and non-coding exons and conserved non-coding elements, in individuals from both families, identified novel mutations in the 5'UTR of RNF113A, which segregate with the disorder in each family, supporting the hypothesis that the families have allelic disorders. This work suggests that regulatory mutations of RNF113A cause a spectrum of skeletal patterning defects with radial aplasia as the common feature. The mutations occur at evolutionarily constrained loci, and the variants disrupt putative transcription factor binding sites. RNF113A encodes a RING finger protein and bioinformatic analysis supports a function as either a Polycomb group protein, and/or an E3-Ubiquitin ligase which may regulate the activity of other Polycomb group proteins. Polycomb group proteins are transcriptional repressors of developmentally important genes, including those with key roles in skeletal patterning (e.g. members of the HOX gene complex). A related gene, RNF115, is located within (or near the breakpoints of) the chromosome 1q21.1 microdeletion associated with TAR (Thrombocytopaenia-Absent Radius) syndrome, which provides additional scope for further work.